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Animal Models of Exercise From Rodents to Pythons
Abstract
Acute and chronic animal models of exercise are commonly used in research. Acute exercise testing is used, often in combination with genetic, pharmacological, or other manipulations, to study the impact of these manipulations on the cardiovascular response to exercise and to detect impairments or improvements in cardiovascular function that may not be evident at rest. Chronic exercise conditioning models are used to study the cardiac phenotypic response to regular exercise training and as a platform for discovery of novel pathways mediating cardiovascular benefits conferred by exercise conditioning that could be exploited therapeutically. The cardiovascular benefits of exercise are well established, and, frequently, molecular manipulations that mimic the pathway changes induced by exercise recapitulate at least some of its benefits. This review discusses approaches for assessing cardiovascular function during an acute exercise challenge in rodents, as well as practical and conceptual considerations in the use of common rodent exercise conditioning models. The case for studying feeding in the Burmese python as a model for exercise-like physiological adaptation is also explored.
... Human walking and running activities may be modeled in rodents through experimental paradigms based on exposure to different kinds of voluntary and involuntary exercise, that can be scheduled to construct an acute or chronic model [74]. The exposure to voluntary aerobic activity is typically carried out by means of running wheels or an equivalent tool, such as an angled rotating running track [21]. ...
In the brain and cognitive reserves framework, aerobic exercise is considered as a protective lifestyle factor able to induce positive effects on both brain structure and function. However, specific aspects of such a beneficial effect still need to be completely clarified. To this aim, the present narrative review focused on the potential brain/cognitive/neural reserve–construction mechanisms triggered by different aerobic exercise types (land activities; such as walking or running; vs. water activities; such as swimming), by considering human and animal studies on healthy subjects over the entire lifespan. The literature search was conducted in PubMed database. The studies analyzed here indicated that all the considered kinds of activities exert a beneficial effect on cognitive/behavioral functions and on the underlying brain neurobiological processes. In particular, the main effects observed involve the cognitive domains of memory and executive functions. These effects appear related to structural and functional changes mainly involving the fronto-hippocampal axis. The present review supports the requirement of further studies that investigate more specifically and systematically the effects of each type of aerobic activity, as a basis to plan more effective and personalized interventions on individuals as well as prevention and healthy promotion policies for the general population.
... Voluntary wheel running (VWR) is a rodent model of physical activity that is widely used to study the biological effects of exercise (Greenwood and Fleshner 2019;Hastings et al. 2022;Novak et al. 2012;Sherwin 1998). However, the translational validity of VWR is limited by a lack of understanding of the biological processes driving the behavior. ...
Rationale
Exercise participation remains low despite clear benefits. Rats engage in voluntary wheel running (VWR) that follows distinct phases of acquisition, during which VWR escalates, and maintenance, during which VWR remains stable. Understanding mechanisms driving acquisition and maintenance of VWR could lead to novel strategies to promote exercise. The two phases of VWR resemble those that occur during operant conditioning and, therefore, might involve similar neural substrates. The dorsomedial (DMS) dorsal striatum (DS) supports the acquisition of operant conditioning, whereas the dorsolateral striatum (DLS) supports its maintenance.
Objectives
Here we sought to characterize the roles of DS subregions in VWR. Females escalate VWR and operant conditioning faster than males. Thus, we also assessed for sex differences.
Methods
To determine the causal role of DS subregions in VWR, we pharmacologically inactivated the DMS or DLS of adult, male and female, Long-Evans rats during the two phases of VWR. The involvement of DA receptor 1 (D1)–expressing neurons in the DS was investigated by quantifying cfos mRNA within this neuronal population.
Results
We observed that, in males, the DMS and DLS are critical for VWR exclusively during acquisition and maintenance, respectively. In females, the DMS is also critical only during acquisition, but the DLS contributes to VWR during both VWR phases. DLS D1 neurons could be an important driver of VWR escalation during acquisition.
Conclusions
The acquisition and maintenance of VWR involve unique neural substrates in the DS that vary by sex. Results reveal targets for sex-specific strategies to promote exercise.
The effect of exercise on disease development in hypertrophic cardiomyopathy (HCM) genotype positive individuals is unresolved. Our objective was to test the effect of exercise training initiated prior to phenotype development on cardiac fibrosis, morphology, and function in a mouse model of HCM. Genotype positive Myh6 R403Q mice exposed to cyclosporine A (CsA) for induction of HCM (HCM mice) were allocated to high intensity interval treadmill running or sedentary behavior for 6 weeks. CsA was initiated from week 4 of the protocol. Cardiac imaging and exercise testing were performed at weeks 0, 3, and 6. After protocol completion, arrhythmia provocation was performed in isolated hearts, and left ventricles (LVs) were harvested for molecular biology and histology. Exercised HCM mice ran farther and faster and exhibited attenuated left atrial (LA) dilatation compared to sedentary mice. Exercised HCM mice had no difference in fibrosis compared to sedentary HCM mice despite lower expression of key ECM genes collagen 1 and 3, fibronectin, and lysyl oxidase, accompanied by increased activation of Akt, GSK3b and p38. Exercise did not have negative effects on LV function in HCM mice. Our findings indicate mild beneficial effects of exercise initiated prior to HCM phenotype development, specifically lower ECM gene expression and LA dilatation, and importantly, no detrimental effects.
Swimming is important for promoting and maintaining health, as it can increase the efficiency of the cardiovascular system and decrease the occurrence of cardiovascular diseases. The objective of the present study was to examine whether swimming training could decrease myocardial injury in rats caused by myocardial ischemia/reperfusion (I/R). Sprague-Dawley rats were randomized into four groups, namely the Sham, coronary artery occlusion, swimming training and ischemic preconditioning (IPC) groups. Myocardial I/R was induced in anesthetized male Sprague-Dawley rats by a 40-min occlusion followed by a 3-h reperfusion of the left anterior descending coronary artery. The rats were sacrificed after surgery and their hearts were examined. The results demonstrated that the number of TUNEL-positive nuclei and degree of caspase-3 activation were both significantly increased in the myocardium following myocardial I/R in rats, indicating increased cardiomyocyte apoptosis. On the other hand, swimming training decreased the serum levels of creatine phosphokinase, lactate dehydrogenase and cardiac troponin I, and was associated with reduced histological damage and myocardial infarct size. Furthermore, swimming training also reduced TNF-α levels, caspase-3 activation and enhanced Bcl-2 activation, which decreased the number of apoptotic cells in the myocardium. The findings of the present study showed that swimming training and IPC could similarly decrease myocardial injury following myocardial I/R, and may therefore be used as exercise training to effectively prevent myocardial injury.
Background:
The heart grows in response to pathological and physiological stimuli. The former often precedes cardiomyocyte loss and heart failure; the latter paradoxically protects the heart and enhances cardiomyogenesis. The mechanisms underlying these differences remain incompletely understood. While long noncoding RNAs (lncRNAs) are important in cardiac development and disease, less is known about their roles in physiological hypertrophy or cardiomyogenesis.
Methods:
RNA sequencing was applied to hearts from mice after eight weeks voluntary exercise-induced physiological hypertrophy and cardiomyogenesis or transverse aortic constriction (TAC) for two or eight weeks to induce pathological hypertrophy or heart failure. The top lncRNA candidate was overexpressed in hearts with adeno-associated virus (AAV) vectors and inhibited with antisense locked nucleic acid (LNA)-GapmeRs to examine its function. Downstream effectors were identified through promoter analyses and binding assays. The functional roles of a novel downstream effector, dachsous cadherin-related 2 (DCHS2), were examined through transgenic overexpression in zebrafish and cardiac-specific deletion in Cas9-knockin mice.
Results:
We identified exercise-regulated cardiac lncRNAs, termed lncExACTs. lncExACT1 was evolutionarily conserved and decreased in exercised hearts but increased in human and experimental heart failure. Cardiac lncExACT1 overexpression caused pathological hypertrophy and heart failure, while lncExACT1 inhibition induced physiological hypertrophy and cardiomyogenesis, protecting against cardiac fibrosis and dysfunction. lncExACT1 functioned by regulating microRNA-222, calcineurin signaling, and Hippo/Yap1 signaling through DCHS2. Cardiomyocyte DCHS2 overexpression in zebrafish induced pathological hypertrophy and impaired cardiac regeneration, promoting scarring after injury. In contrast, murine DCHS2 deletion induced physiological hypertrophy and promoted cardiomyogenesis.
Conclusions:
These studies identify lncExACT1-DCHS2 as a novel pathway regulating cardiac hypertrophy and cardiomyogenesis. lncExACT1-DCHS2 acts as a master switch toggling the heart between physiological and pathological growth to determine functional outcomes, providing a potentially tractable therapeutic target for harnessing the beneficial effects of exercise.
Tissue sensitivity and response to exercise vary according to the time of day and alignment of circadian clocks, but the optimal exercise time to elicit a desired metabolic outcome is not fully defined. To understand how tissues independently and collectively respond to timed exercise, we applied a systems biology approach. We mapped and compared global metabolite responses of seven different mouse tissues and serum after an acute exercise bout performed at different times of the day. Comparative analyses of intra- and inter-tissue metabolite dynamics, including temporal profiling and blood sampling across liver and hindlimb muscles, uncovered an unbiased view of local and systemic metabolic responses to exercise unique to time of day. This comprehensive atlas of exercise metabolism provides clarity and physiological context regarding the production and distribution of canonical and novel time-dependent exerkine metabolites, such as 2-hydroxybutyrate (2-HB), and reveals insight into the health-promoting benefits of exercise on metabolism.
Inbred and genetically modified mice are frequently used to investigate the molecular mechanisms responsible for the beneficial adaptations to exercise training. However, published paradigms for exercise training in mice are variable, making comparisons across studies for training efficacy difficult. The purpose of this systematic review and meta-analysis was to characterize the diversity across published treadmill-based endurance exercise training protocols for mice and to identify training protocol parameters that moderate the adaptations to endurance exercise training in mice. Published studies were retrieved from PubMed and EMBASE and reviewed for the following inclusion criteria: inbred mice; inclusion of a sedentary group; and exercise training using a motorized treadmill. Fifty-eight articles met those inclusion criteria and also included a “classical” marker of training efficacy. Outcome measures included changes in exercise performance, V ˙ O 2max , skeletal muscle oxidative enzyme activity, blood lactate levels, or exercise-induced cardiac hypertrophy. The majority of studies were conducted using male mice. Approximately 48% of studies included all information regarding exercise training protocol parameters. Meta-analysis was performed using 105 distinct training groups (i.e., EX-SED pairs). Exercise training had a significant effect on training outcomes, but with high heterogeneity (Hedges’ g =1.70, 95% CI=1.47–1.94, Tau ² =1.14, I ² =80.4%, prediction interval=−0.43–3.84). Heterogeneity was partially explained by subgroup differences in treadmill incline, training duration, exercise performance test type, and outcome variable. Subsequent analyses were performed on subsets of studies based on training outcome, exercise performance, or biochemical markers. Exercise training significantly improved performance outcomes (Hedges’ g =1.85, 95% CI=1.55–2.15). Subgroup differences were observed for treadmill incline, training duration, and exercise performance test protocol on improvements in performance. Biochemical markers also changed significantly with training (Hedges’ g =1.62, 95% CI=1.14–2.11). Subgroup differences were observed for strain, sex, exercise session time, and training duration. These results demonstrate there is a high degree of heterogeneity across exercise training studies in mice. Training duration had the most significant impact on training outcome. However, the magnitude of the effect of exercise training varies based on the marker used to assess training efficacy.
Exercise training has been reported to alleviate cardiac fibrosis and ameliorate heart dysfunction after myocardial infarction (MI), but the molecular mechanism is still not fully clarified. Fibroblast growth factor 21 (FGF21) exerts a protective effect on the infarcted heart. This study investigates whether exercise training could increase FGF21 protein expression and regulate the transforming growth factor-β1 (TGF-β1)-Smad2/3-MMP2/9 signaling pathway to alleviate cardiac fibrosis following MI. Male wild type (WT) C57BL/6J mice and Fgf21 knockout (Fgf21 KO) mice were used to establish the MI model and subjected to five weeks of different types of exercise training. Both aerobic exercise training (AET) and resistance exercise training (RET) significantly alleviated cardiac dysfunction and fibrosis, up-regulated FGF21 protein expression, inhibited the activation of TGF-β1-Smad2/3-MMP2/9 signaling pathway and collagen production, and meanwhile, enhanced antioxidant capacity and reduced cell apoptosis in the infarcted heart. In contrast, knockout of Fgf21 weakened the cardioprotective effects of AET after MI. In vitro, cardiac fibroblasts (CFs) were isolated from neonatal mice hearts and treated with H2O2 (100 μM, 6 h). Recombinant human FGF21 (rhFGF21, 100 ng/mL, 15 h) and/or 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR, 1 mM, 15 h) inhibited H2O2-induced activation of the TGF-β1-Smad2/3-MMP2/9 signaling pathway, promoted CFs apoptosis and reduced collagen production. In conclusion, exercise training increases FGF21 protein expression, inactivates the TGF-β1-Smad2/3-MMP2/9 signaling pathway, alleviates cardiac fibrosis, oxidative stress, and cell apoptosis, and finally improves cardiac function in mice with MI. FGF21 plays an important role in the anti-fibrosis effect of exercise training.
Aging is the most important risk factor for cardiovascular diseases. Although exercise is known to be beneficial for the health of aging heart, the optimal exercise training intensity to prevent natural aging-induced cardiac damage has not been defined. In this study, we used 32-week-old male mice and randomly divided them into three groups, namely, untrained (UNT) mice, moderate-intensity exercise training (MET) mice, and high-intensity interval training (HIIT) mice. Mice in the two exercise training groups were subjected to exercise 5 days per week for 24 consecutive weeks. Metabolic characteristics, cardiac function and morphology, myocardial remodeling, myocardial fibrosis (collagen III, α-SMA, and TGF-β), oxidative stress (NRF2, HO-1, SOD, and NOX4), and apoptosis (BAX, Bak, Bcl-2, and Bcl-XL) were analyzed 24 weeks after the different treatments. MET improved cardiac function and reduced myocardial remodeling, myocardial fibrosis, and oxidative stress in the aging heart. MET treatment exerted an anti-apoptotic effect in the heart of the aging mice. Importantly, HIIT did not protect against cardiac damage during the natural aging process. These findings suggest that MET may be one of the main methods to prevent cardiac damage induced by natural aging.
Doxorubicin causes cardiotoxicity and exercise intolerance. Pre-conditioning exercise training seems to prevent doxorubicin-induced cardiac damage. However, the effectiveness of the cardioprotective effects of exercise training concomitantly with doxorubicin treatment remains largely unknown. To determine whether low-to-moderate intensity aerobic exercise training during doxorubicin treatment would prevent cardiotoxicity and exercise intolerance, we performed exercise training concomitantly with chronic doxorubicin treatment in mice. Ventricular structure and function were accessed by echocardiography, exercise tolerance by maximal exercise test, and cardiac biology by histological and molecular techniques. Doxorubicin-induced cardiotoxicity, evidenced by impaired ventricular function, cardiac atrophy, and fibrosis. Exercise training did not preserve left ventricular ejection fraction or reduced fibrosis. However, exercise training preserved myocardial circumferential strain alleviated cardiac atrophy and restored cardiomyocyte cross-sectional area. On the other hand, exercise training exacerbated doxorubicin-induced body wasting without affecting survival. Finally, exercise training blunted doxorubicin-induced exercise intolerance. Exercise training performed during doxorubicin-based chemotherapy can be a valuable approach to attenuate cardiotoxicity.
Aims
Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent disease. Physical exercise has been shown to alter disease progression in HFpEF. We examined cardiomyocyte Ca²⁺ homeostasis and left ventricular function in a metabolic HFpEF model in sedentary and trained rats following 8 weeks of moderate‐intensity continuous training (MICT) or high‐intensity interval training (HIIT).
Methods and results
Left ventricular in vivo function (echocardiography) and cardiomyocyte Ca²⁺ transients (CaTs) (Fluo‐4, confocal) were compared in ZSF‐1 obese (metabolic syndrome, HFpEF) and ZSF‐1 lean (control) 21‐ and 28‐week‐old rats. At 21 weeks, cardiomyocytes from HFpEF rats showed prolonged Ca²⁺ reuptake in cytosolic and nuclear CaTs and impaired Ca²⁺ release kinetics in nuclear CaTs. At 28 weeks, HFpEF cardiomyocytes had depressed CaT amplitudes, decreased sarcoplasmic reticulum (SR) Ca²⁺ content, increased SR Ca²⁺ leak, and elevated diastolic [Ca²⁺] following increased pacing rate (5 Hz). In trained HFpEF rats (HIIT or MICT), cardiomyocyte SR Ca²⁺ leak was significantly reduced. While HIIT had no effects on the CaTs (1–5 Hz), MICT accelerated early Ca²⁺ release, reduced the amplitude, and prolonged the CaT without increasing diastolic [Ca²⁺] or cytosolic Ca²⁺ load at basal or increased pacing rate (1–5 Hz). MICT lowered pro‐arrhythmogenic Ca²⁺ sparks and attenuated Ca²⁺‐wave propagation in cardiomyocytes. MICT was associated with increased stroke volume in HFpEF.
Conclusions
In this metabolic rat model of HFpEF at an advanced stage, Ca²⁺ release was impaired under baseline conditions. HIIT and MICT differentially affected Ca²⁺ homeostasis with positive effects of MICT on stroke volume, end‐diastolic volume, and cellular arrhythmogenicity.
Aim: Dysfunction of the cardiac ryanodine receptor (RyR2) is an almost ubiquitous finding in animal models of heart failure (HF) and results in abnormal Ca ²⁺ release in cardiomyocytes that contributes to contractile impairment and arrhythmias. We tested whether exercise training (ET), as recommended by current guidelines, had the potential to stabilize RyR2-dependent Ca ²⁺ release in rats with post-myocardial infarction HF.
Materials and Methods: We subjected male Wistar rats to left coronary artery ligation or sham operations. After 1 week, animals were characterized by echocardiography and randomized to high-intensity interval ET on treadmills or to sedentary behavior (SED). Running speed was adjusted based on a weekly VO 2max test. We repeated echocardiography after 5 weeks of ET and harvested left ventricular cardiomyocytes for analysis of RyR2-dependent systolic and spontaneous Ca ²⁺ release. Phosphoproteins were analyzed by Western blotting, and beta-adrenoceptor density was quantified by radioligand binding.
Results: ET increased VO 2max in HF-ET rats to 127% of HF-SED ( P < 0.05). This coincided with attenuated spontaneous SR Ca ²⁺ release in left ventricular cardiomyocytes from HF-ET but also reduced Ca ²⁺ transient amplitude and slowed Ca ²⁺ reuptake during adrenoceptor activation. However, ventricular diameter and fractional shortening were unaffected by ET. Analysis of Ca ²⁺ homeostasis and major proteins involved in the regulation of SR Ca ²⁺ release and reuptake could not explain the attenuated spontaneous SR Ca ²⁺ release or reduced Ca ²⁺ transient amplitude. Importantly, measurements of beta-adrenoceptors showed a normalization of beta 1 -adrenoceptor density and beta 1 :beta 2 -adrenoceptor ratio in HF-ET.
Conclusion: ET increased aerobic capacity in post-myocardial infarction HF rats and stabilized RyR2-dependent Ca ²⁺ release. Our data show that these effects of ET can be gained without major alterations in SR Ca ²⁺ regulatory proteins and indicate that future studies should include upstream parts of the sympathetic signaling pathway.
Background:
Exercise training is beneficial for cardiac rehabilitation. Nevertheless, few study focused on the role of high-intensity interval training (HIIT) in cardiac repair. The current study aimed to elucidate the effect of HIIT on cardiac rehabilitation and the involved mechanisms after acute myocardial infarction (MI).
Methods:
A total of 65 male rats underwent coronary ligation or sham operation and were randomly assigned to 4 groups: sham (n = 10), sedentary (MI-Sed, n = 12), moderate-intensity continuous training (MI-MCT, n = 12) and HIIT (MI-HIIT, n = 12). One week after MI induction, adaptive training starts follow by formal training. After the experiment, cardiac functions were determined by echocardiography and hemodynamic measurements. Changes in infarct size, collagen accumulation, myofibroblasts, angiogenesis, inflammation level, endothelin-1 (ET-1), and renin-angiotensin-aldosterone system (RAAS) activities were measured. Data were analyzed by one-way ANOVA.
Results:
After MI, cardiac structure and function were significantly deteriorated. However, post-MI HIIT for 8 weeks had significantly ameliorated left ventricular end-diastolic pressure (LVEDP), LV systolic pressure (LVSP), and maximum peak velocities of relaxation (-dP/dtmax). Moreover, it preserved cardiac functions, reduced infarct size, protected the myocardium structure, increased angiogenesis and decreased the myofibroblasts and collagen accumulation. HIIT for 4 weeks had no effect on LVEDP, -dP/dtmax, infarct size and angiogenesis. Additionally, it induced inflammation response and repressed ET-1 and RAAS activities were found in myocardium and peripheral circulation after HIIT.
Conclusion:
Our results suggested that post-MI HIIT had a positive role in cardiac repair, which might be linked with the induction of inflammation and inhibition of ET-1 and RAAS activities.
We investigated the effects of voluntary exercise after myocardial infarction (MI) on cardiac function, remodeling, and inflammation. Male C57BL/6J mice were divided into the following four groups: sedentary + sham (Sed-Sh), sedentary + MI (Sed-MI), exercise + sham (Ex-Sh), and exercise + MI (Ex-MI). MI induction was performed by ligation of the left coronary artery. Exercise consisting of voluntary wheel running started after the operation and continued for 4 weeks. The Ex-MI mice had significantly increased cardiac function compared with the Sed-MI mice. The Ex-MI mice showed significantly reduced expression levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-10 in the infarcted area of the left ventricle compared with the Sed-MI mice. In the Ex-MI mice, the expression levels of fibrosis-related genes including collagen I and III were decreased compared to the Sed-MI mice, and the expression levels of IL-1β, IL-6, follistatin-like 1, fibroblast growth factor 21, and mitochondrial function-related genes were significantly elevated in skeletal muscle compared with the Sed mice. The plasma levels of IL-6 were also significantly elevated in the Ex-MI group compared with the Sed-MI groups. These findings suggest that voluntary exercise after MI may improve in cardiac remodeling associated with anti-inflammatory effects in the myocardium and myokine production in the skeletal muscles.
Heart failure with preserved ejection fraction (HFpEF) is the most common type of HF in older adults. Although no pharmacological therapy has yet improved survival in HFpEF, exercise training (ExT) has emerged as the most effective intervention to improving functional outcomes in this age‐related disease. The molecular mechanisms by which ExT induces its beneficial effects in HFpEF, however, remain largely unknown. Given the strong association between aging and HFpEF, we hypothesized that ExT might reverse cardiac aging phenotypes that contribute to HFpEF pathophysiology and additionally provide a platform for novel mechanistic and therapeutic discovery. Here, we show that aged (24–30 months) C57BL/6 male mice recapitulate many of the hallmark features of HFpEF, including preserved left ventricular ejection fraction, subclinical systolic dysfunction, diastolic dysfunction, impaired cardiac reserves, exercise intolerance, and pathologic cardiac hypertrophy. Similar to older humans, ExT in old mice improved exercise capacity, diastolic function, and contractile reserves, while reducing pulmonary congestion. Interestingly, RNAseq of explanted hearts showed that ExT did not significantly modulate biological pathways targeted by conventional HF medications. However, it reversed multiple age‐related pathways, including the global downregulation of cell cycle pathways seen in aged hearts, which was associated with increased capillary density, but no effects on cardiac mass or fibrosis. Taken together, these data demonstrate that the aged C57BL/6 male mouse is a valuable model for studying the role of aging biology in HFpEF pathophysiology, and provide a molecular framework for how ExT potentially reverses cardiac aging phenotypes in HFpEF.
Doxorubicin (DOX) is known as an effective drug in the fight against various cancers. However, one of the greatest impediments is DOX-induced cardiomyopathy, which may potentially lead to heart failure. Accumulating evidence has shed light on the pathological mechanism of DOX-induced cardiotoxicity, but treatments to mitigate the cardiac damage are still required. In an attempt to address this issue, we evaluated whether exercise provides cardioprotective effects on the DOX-induced cardiotoxicity. We showed that treadmill exercise (3 times/week; 1-week of exercise acclimatization and 4-weeks of endurance exercise) during the DOX treatment successfully prevented the cardiac dysfunction. The DOX-stimulated expression of IκBα, NF-κB, COX-2, and IL-8 were all downregulated by exercise as well as the fibrosis factors (TGF-β1, phosphorylated ERK, Sp1, and CTGF). Moreover, we showed that treadmill exercise diminished the expression of several cardiac remodeling-associated factors, such as FGF2, uPA, MMP2, and MMP9. These results were in line with the finding that exercise intervention reduced cardiac fibrosis and restored cardiac function, with higher values of ejection fraction and fractional shortening compared to the DOX-treated group. Two commonly used indicators of cardiac injury, lactate dehydrogenase, and creatine kinase-MB, were also decreased in the exercise group. Collectively, our results suggested that it may be beneficial to prescribe treadmill exercise as an adjunct therapy to limit cardiac damage caused by DOX.
Recent study has demonstrated that high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) have the same effect to alleviate β-amyloid pathology in the hippocampus of APPswe/PS1dE9 (APP/PS1) mice. Activation of nucleotide binding and oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is pivotal and has been demonstrated to accelerate β-amyloid accumulation. The present study aimed to examine whether the exercise-induced β-amyloid reduction was associated with changes in NLRP3 inflammasome activation. APP/PS1 transgenic mice were randomly assigned to a transgenic sedentary group, HIIT group and MICT group. Nontransgenic littermates were used as wild-type sedentary group. Mice in HIIT and MICT groups were subjected to treadmill exercise for 12 weeks, 5 days/week. The results showed that compared with transgenic sedentary group, β-amyloid deposition in the hippocampus of HIIT and MICT groups were significantly reduced. Moreover, both HIIT and MICT groups displayed significant increases in the expression of microglial phagocytic receptors triggering receptor expressed on myeloid cells 2, CD36 and scavenger receptor class A compared with transgenic sedentary group. In addition, HIIT and MICT had the same effect to inhibit NLRP3 inflammasome activation, as evidenced by significant reduction in IL-1β, active caspase-1p20, NLRP3 and apoptosis-associated speck-like protein containing a caspase activating and recruitment domain (ASC) levels as well as decreased NLRP3/ASC colocalization. These findings indicate that HIIT appears to be an effective intervention as MICT to reduced β-amyloid deposition by regulating NLRP3 inflammasome-controlled microglial phagocytosis.
Aerobic exercise is well known to have a positive impact on body composition, muscle strength, and oxidative capacity. In animal model, both treadmill and wheel running exercise modalities have become more popular, in order to study physiological adaptation associated with aerobic exercise. However, few studies have compared physiological adaptations in response to either treadmill exercise (TE), or voluntary wheel running exercise (WE). We therefore compared each exercise intervention on body composition and oxidative markers in male C57BL/6 N mice. The total distance run was remarkably higher in the WE group than in the TE group. Both forms of exercise resulted in the reduction of body weight, fat mass, and adipocyte size. However, the average for grip strength of WE was higher than for control and TE. Interestingly, PGC-1α expression was increased in the gastrocnemius (glycolytic-oxidative) and soleus (oxidative) muscle of TE group, whereas WE showed a significant effect on PGC-1α expression only in the soleus muscle. However, muscle fiber type composition was not shifted remarkably in either type of exercise. These results suggest that TE and WE may exert beneficial effects in suppressing metabolic risks in mouse model through attenuating body weight, fat mass, size, and increase in mitochondria biogenesis marker, PGC-1α.
Background
Exercise is considered as an important intervention for treatment and prevention of several diseases, such as osteoarthritis, obesity, hypertension, and Alzheimer's disease. This review summarizes decadal exercise intervention studies with various rat models across 6 major systems to provide a better understanding of the mechanisms behind the effects that exercise brought.
Methods
PubMed was utilized as the data source. To collect research articles, we used the following terms to create the search: (exercise [Title] OR physical activity [Title] OR training [Title]) AND (rats [Title/Abstract] OR rat [Title/Abstract] OR rattus [Title/Abstract]). To best cover targeted studies, publication dates were limited to “within 11 years.” The exercise intervention methods used for different diseases were sorted according to the mode, frequency, and intensity of exercise.
Results
The collected articles were categorized into studies related to 6 systems or disease types: motor system (17 articles), metabolic system (110 articles), cardiocerebral vascular system (171 articles), nervous system (71 articles), urinary system (2 articles), and cancer (21 articles). Our review found that, for different diseases, exercise intervention mostly had a positive effect. However, the most powerful effect was achieved by using a specific mode of exercise that addressed the characteristics of the disease.
Conclusion
As a model animal, rats not only provide a convenient resource for studying human diseases but also provide the possibility for exploring the molecular mechanism of exercise intervention in diseases. This review also aims to provide exercise intervention frameworks and optimal exercise dose recommendations for further human exercise intervention research.
Physical activity is an efficient strategy to delay development of obesity and insulin resistance, and thus the progression of obesity/diabetes-related cardiomyopathy. In support of this, experimental studies using animal models of obesity show that chronic exercise prevents the development of obesity-induced cardiac dysfunction (cardiomyopathy). Whether exercise also improves the tolerance to ischemia-reperfusion in these models is less clear, and may depend on the type of exercise procedure as well as time of initiation. We have previously shown a reduction in ischemic-injury in diet-induced obese mice, when the exercise was started prior to the development of cardiac dysfunction in this model. In the present study, we aimed to explore the effect of exercise on ischemic-tolerance when exercise was initiated after the development obesity-mediated. Male C57BL/6J mice were fed a high-fat diet (HFD) for 20–22 weeks, where they were subjected to high-intensity interval training (HIT) during the last 3 weeks of the feeding period. Sedentary HFD fed and chow fed mice served as controls. Left-ventricular (LV) post-ischemic functional recovery and infarct size were measured in isolated perfused hearts. We also assessed the effect of 3-week HIT on mitochondrial function and myocardial oxygen consumption (MVO2). Sedentary HFD fed mice developed marked obesity and insulin resistance, and demonstrated reduced post-ischemic cardiac functional recovery and increased infarct size. Three weeks of HIT did not induce cardiac hypertrophy and only had a mild effect on obesity and insulin resistance. Despite this, HIT improved post-ischemic LV functional recovery and reduced infarct size. This increase in ischemic-tolerance was accompanied by an improved mitochondrial function as well as reduced MVO2. The present study highlights the beneficial effects of exercise training with regard to improving the ischemic-tolerance in hearts with cardiomyopathy following obesity and insulin resistance. This study also emphasizes the exercise-induced improvement of cardiac energetics and mitochondrial function in obesity/diabetes.
Exercise has an effect on the reduction of myocardial fibrosis in diabetic rats as previously reported, in which oxidative stress and the TGF-β1/Smad signaling pathway may play key roles. There is little direct experimental evidence that exercise alleviates myocardial fibrosis in type 2 diabetes mellitus (T2DM). Here we established a type 2 diabetic model by using streptozotocin and a high-fat diet. Rats were divided into groups of normal control (NC), T2DM and T2DM plus exercise (T2DME). The T2DME group received further treadmill training at moderate intensity for 8 weeks. Histological and biochemical methods were used to detect the benefits of exercise to T2DM. Results showed that the weight of rats in the T2DM group dropped dramatically, along with significant increases in blood glucose, myocardial fibrosis and oxidative stress, associated with upregulated expression of factors of myocardial fibrosis, except Smad7. Exercise largely reversed T2DM-induced alterations in factors of myocardial fibrosis, including suppressing expression of MMP-2, CTGF, TGF-β1, p-Smad2 and p-Smad3, and increased expression of TIMP–1 and Smad7. Therefore, exercise might be considered an alternative therapeutic remedy for diabetic cardiomyopathy.
Background:
In recent years, much evidence has emerged to indicate that exercise can benefit people when performed properly. This review summarizes the exercise interventions used in studies involving mice as they are related to special diseases or physiological status. To further understand the effects of exercise interventions in treating or preventing diseases, it is important to establish a template for exercise interventions that can be used in future exercise-related studies.
Methods:
PubMed was used as the data resource for articles. To identify studies related to the effectiveness of exercise interventions for treating various diseases and organ functions in mice, we used the following search language: (exercise [Title] OR training [Title] OR physical activity [Title]) AND (mice [title/abstract] OR mouse [title/abstract] OR mus [title/abstract]). To limit the range of search results, we included 2 filters: one that limited publication dates to "in 10 years" and one that sorted the results as "best match". Then we grouped the commonly used exercise methods according to their similarities and differences. We then evaluated the effectiveness of the exercise interventions for their impact on diseases and organ functions in 8 different systems.
Results:
A total of 331 articles were included in the analysis procedure. The articles were then segmented into 8 systems for which the exercise interventions were used in targeting and treating disorders: motor system (60 studies), metabolic system (45 studies), cardio-cerebral vascular system (58 studies), nervous system (74 studies), immune system (32 studies), respiratory system (7 studies), digestive system (1 study), and the system related to the development of cancer (54 studies). The methods of exercise interventions mainly involved the use of treadmills, voluntary wheel-running, forced wheel-running, swimming, and resistance training. It was found that regardless of the specific exercise method used, most of them demonstrated positive effects on various systemic diseases and organ functions. Most diseases were remitted with exercise regardless of the exercise method used, although some diseases showed the best remission effects when a specific method was used.
Conclusion:
Our review strongly suggests that exercise intervention is a cornerstone in disease prevention and treatment in mice. Because exercise interventions in humans typically focus on chronic diseases, national fitness, and body weight loss, and typically have low intervention compliance rates, it is important to use mice models to investigate the molecular mechanisms underlying the health benefits from exercise interventions in humans.
Background
Myocardial ischemia-reperfusion (IR) injury is a leading cause of death all over the world, so developing practical approaches to promote cardioprotection against IR injury is essential. Exercise training is an effective strategy to improve cardioprotection. Hence, the purpose of this study was to investigate the effect of short-term preconditioning with two types of high-intensity interval training (HIIT) and moderate intensity continuous training (MICT) on klotho and TRPC6 mechanisms in cardioprotection.
Methods
Eighty Male Wistar rats (250–300 g) were randomly divided into 7 groups, including Control, HIIT, MICT, Sham, IR, HIIT+IR, and MICT+IR. Training was performed in 5 consecutive days. HIIT protocol consisted of running on the treadmill at intervals 85–90% vo2max that separated by slow intensity periods at 50–60% vo2max. MICT program was performed at 70% VO2max at the same running distance with HIIT groups. The cardiac IR injury was induced by LAD occlusion followed by reperfusion. ELISA kit was used in order to measure the plasma levels of klotho, LDH and CK-MB, and TRPC6 expression was determined using the western blot technique. Data were analyzed using one way ANOVA and Tukey’s post hoc tests.
Results
The results of this study showed that both types of exercise training programs significantly increase plasma levels of klotho and reduce the infarct size and heart injury. In addition, the exercise training decreased the amount of TRPC6 channels expression during IR. However, the effect of HIIT on increasing the klotho and cardioprotection was greater compared to MICT.
Conclusions
Based on the results, even a short-term of aerobic exercise training, especially HIIT, promotes cardioprotection against IR injury and decreases infarct size via an increase in klotho and attenuate of protein expression of myocardial TRPC6 during IR.
Exercise training is a low cost and safe approach for reducing the risk of cardiovascular disease development. Currently, moderate-intensity training (MIT) is the most preferred exercise type. However, high-intensity interval training (HIIT) is gaining interest especially among athletes and healthy individuals. In this study, we examined cardiac remodeling resulting from MIT and HIIT in healthy rats. Healthy male Sprague-Dawley rats were randomly assigned to MIT or HIIT for 13 weeks. Animals kept sedentary (SED) were used as control. Cardiac function was evaluated with echocardiography and hemodynamic measurements. Heart tissue was stained for capillary density and fibrosis. After 13 weeks of training, only HIIT induced beneficial cardiac hypertrophy. Overall global cardiac parameters (such as ejection fraction, cardiac output and volumes) were improved similarly between both training modalities. At tissue level, collagen content was significantly and similarly reduced in both exercise groups. Finally, only HIIT increased significantly capillary density. Our data indicate that even if very different in design, HIIT and MIT appear to be equally effective in improving cardiac function in healthy rats. Furthermore, HIIT provides additional benefits through improved capillary density and should therefore be considered as a preferred training modality for athletes and for patients.
Diastolic dysfunction is a common complication that occurs early in diabetes mellitus. Titin and collagen are two important regulators of myocardial passive tension, which contributes to diabetic myocardial diastolic dysfunction. Exercise therapy significantly improves the impaired diabetic cardiac function, but its benefits appear to depend on the type of exercise used. We investigated the effect of aerobic and resistance exercise on cardiac diastolic function in diabetic rats induced by high-fat diet combined with low-dose streptozotocin injection. Interestingly, although resistance training had a more pronounced effect on blood glucose control than did aerobic training in type 2 diabetic rats, improvements in cardiac diastolic parameters benefited more from aerobic training. Moreover, aerobic exercise did significantly increase the expression levels of titin and decrease collagen I, TGFβ1 expression level. In summary, out data suggest that aerobic exercise may improve diabetic cardiac function through changes in titin-dependent myocardial stiffness rather than collagen-dependent interstitial fibrosis.
Background: Physical exercise is suspected to reduce cancer risk and mortality. So far, little is known about the underlying mechanisms. Although limited, murine models represent a promising attempt in order to gain knowledge in this field.
Objective: A systematic review and meta-analysis examining various treatment protocols was conducted in order to determine the impact of exercise on tumor growth in rodents.
Methods: PubMed, Google scholar and System for information on Gray literature in Europe were screened from inception to October 2017. Risk of bias within individual studies was assessed using the Office of Health Assessment and Translation risk of bias rating tool for human and animal trials. The effect of exercise on tumor growth over and above non-exercise control was pooled using random-effects model. Subgroup analyses were conducted to identify potential moderators.
Results: The quality of the included 17 articles ranged between “probably low” and “high risk of bias.” A significant reduction in tumor growth in exercising animals compared to controls was detected (Hedges' g = −0.40; 95% CI −0.66 to −0.14, p < 0.01) with between-study heterogeneity (τ² = 0.217, I² = 70.28%, p < 0.001). The heterogeneity was partially explained by three moderators representing the in-between group differences of “maximum daily exercise” R² = 33% (p < 0.01), “type of cancer administration” R² = 28% (p < 0.05), and “training initiation” R² = 27% (p < 0.05).
Conclusion: This meta-analysis suggests that physical exercise leads to reduction of tumor size in rodents. Since “maximum daily exercise” was found to have at least modest impact on tumor growth, more clinical trials investigating dose-response relationships are needed.
Loss of cardiomyocytes is a major cause of heart failure, and while the adult heart has a limited capacity for cardiomyogenesis, little is known about what regulates this ability or whether it can be effectively harnessed. Here we show that 8 weeks of running exercise increase birth of new cardiomyocytes in adult mice (~4.6-fold). New cardiomyocytes are identified based on incorporation of 15N-thymidine by multi-isotope imaging mass spectrometry (MIMS) and on being mononucleate/diploid. Furthermore, we demonstrate that exercise after myocardial infarction induces a robust cardiomyogenic response in an extended border zone of the infarcted area. Inhibition of miR-222, a microRNA increased by exercise in both animal models and humans, completely blocks the cardiomyogenic exercise response. These findings demonstrate that cardiomyogenesis can be activated by exercise in the normal and injured adult mouse heart and suggest that stimulation of endogenous cardiomyocyte generation could contribute to the benefits of exercise.
Background
Exercise benefits to cardiac rehabilitation (CR) following stable myocardial infarction (MI). The suitable exercise duration for aged patients with coronary heart disease (CHD) remains controversial, and the underlying molecular mechanism is still unclear.
Methods and Results
18-Month-old mice after stable MI were randomly submitted to different durations of exercise, including 15 and 60 min swimming training (ST) once per day, five times a week for 8 weeks. Compared to sedentary mice, 15 min ST, rather than 60 min ST, significantly augmented left ventricular function, increased survival rate, and suppressed myocardial fibrosis and apoptosis. 15 min ST improved mitochondrial morphology via regulating mitochondrial fission-fusion signaling. 15 min ST regulated mitophagy signaling via inhibiting LC3-II and P62 levels and increasing PINK/Parkin expression. 15 min ST also inhibited ROS production and enhanced antioxidant SOD2 activity. Notably, 15 min ST significantly increased sirtuin (SIRT) 3 level (2.7-fold) in vivo while the inhibition of SIRT3 exacerbated senescent H9c2 cellular LDH release and ROS production under hypoxia. In addition, SIRT3 silencing impairs mitochondrial dynamics and mitophagy in senescent cardiomyocytes against simulated ischemia (SI) injury.
Conclusion
Collectively, our study demonstrated for the first time that sustained short-duration exercise, rather than long-duration exercise, attenuates cardiac dysfunction after MI in aged mice. It is likely that the positive regulation induced by a short-duration ST regimen on the elevated SIRT3 protein level improved mitochondrial quality control and decreased apoptosis and fibrosis contributed to the observed more resistant phenotype.
Cardiovascular disease is a leading cause of death, and translational research is needed to understand better mechanisms whereby the left ventricle responds to injury. Mouse models of heart disease have provided valuable insights into mechanisms that occur during cardiac aging and in response to a variety of pathologies. The assessment of cardiovascular physiological responses to injury or insult is an important and necessary component of this research. With increasing consideration for rigor and reproducibility, the goal of this guidelines review is to provide best-practice information regarding how to measure accurately cardiac physiology in animal models. In this article, we define guidelines for the measurement of cardiac physiology in mice, as the most commonly used animal model in cardiovascular research.
Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/guidelines-for-measuring-cardiac-physiology-in-mice/.
Elevated salt intake induces changes in the extracellular matrix collagen, leading to myocardial stiffness and impaired relaxation. Resistance training (RT) has been used as a remarkably successful strategy in the treatment of heart disease. Therefore, the aim of this study was to investigate the effects of RT on preventing pathological adaptation of the left ventricle (LV) induced by salt overload. Male Wistar rats (10 weeks old) were distributed into four groups (n=8/group): control (CO), control+1% salt (CO+SALT), RT and RT+1% salt (RT+SALT). The RT protocol consisted of 4×12 bouts of squat training, 5/week for 8 weeks, with 80% of one repetition maximum (1RM). Echocardiographs were analyzed and interstitial collagen volume fraction (CVF) was determined in the LV. The 1RM tests in the RT and RT+SALT groups increased 145 and 137%, respectively, compared with the test performed before the training program. LV weight-to-body weight ratio and LV weight-to-tibia length ratio were greater in the RT and RT+SALT groups, respectively, compared with the CO group. Although there was no difference in the systolic function between groups, diastolic function decreased 25% in the CO+SALT group compared with the CO group measured by E/A wave ratio. RT partially prevented this decrease in diastolic function compared with the CO+SALT group. A 1% salt overload increased CVF more than 2.4-fold in the CO+SALT group compared with the CO group and RT prevented this increase. In conclusion, RT prevented interstitial collagen deposition in LV rats subjected to 1% NaCl and attenuated diastolic dysfunction induced by salt overload independent of alterations in blood pressure.
Background: Exceptional and extreme feeding behaviour makes the Burmese python (Python bivittatus) an interesting model to study physiological remodelling and metabolic adaptation in response to refeeding after prolonged starvation. In this study, we used transcriptome sequencing of five visceral organs during fasting as well as 24h and 48h after ingestion of a large meal to unravel the postprandial changes in Burmese pythons. We first used the pooled data to perform a de novo assembly of the transcriptome and supplemented this with a proteomic survey of enzymes in the plasma and gastric fluid.
Results: We constructed a high-quality transcriptome with 34,423 transcripts of which 19,713 (57%) were annotated. Among highly expressed genes (FPKM>100 in one tissue) we found the transition from fasting to digestion was associated with differential expression of 43 genes in the heart, 206 genes in the liver, 114 genes in the stomach, 89 genes in the pancreas and 158 genes in the intestine. We interrogated the function of these genes to test previous hypotheses on the response to feeding. We also used the transcriptome to identify 314 secreted proteins in the gastric fluid of the python.
Conclusions: Digestion was associated with an upregulation of genes related to metabolic processes, and translational changes therefore appears to support the postprandial rise in metabolism. We identify stomach-related proteins from a digesting individual and demonstrate that the sensitivity of modern LC-MS/MS equipment allows the identification of gastric juice proteins that are present during digestion.
Background
Aging decreases ischemic tolerance, while exercise prevents myocardial ischemia reperfusion (IR) injury. The cardioprotective role of high intensity interval training (HIIT), however, is unknown.
Methods
Accordingly, we investigated 8 weeks (5 days/week, 40 min/day) of HIIT treadmill exercise (60%/90% of VO2 peak) on IR injury in young (2-month) and senescent (20-month) Wistar rat myocardia (N = 10/group). Surgical IR (30 min/120 min) was performed via reversible left anterior descending artery ligation and ECG was analyzed to determine ventricular ectopy during IR period.
Results
Infarction size and oxidative stress were measured in hearts post-mortem. Glutathione peroxidase activity and Myeloperoxidase levels were mitigated with age, but elevated post IR. HIIT potentiated antioxidant defenses in young and old hearts, and infarction size was lower in young HIIT trained. Metrics of reactive oxygen species were not lower after IR, and were not affected by HIIT in young or old rats. Ventricular ectopy score in senescent rats was insignificantly more than young rats and HIIT significantly decreased ventricular ectopy score in young and senescent rats.
Conclusions
Findings indicate that IR tolerance is mitigated in senescent hearts, while HIIT ameliorated infarction by increasing antioxidant enzymes activity in young and senescent hearts.
Background: Exercise training's benefits in cardiovascular system have been well accepted, however, the underlying mechanism remains to be explored. Here, we report the initial functional characterization of an exercise-induced cardiac physiological hypertrophy associated novel lncRNA.
Methods: Using lncRNA microarray profiling, we identified lncRNAs in contributing the modulation of exercise-induced cardiac growth that we termed Cardiac Physiological hypertrophy associated regulator (CPhar). Mice with Adeno-associated virus serotype 9 (AAV9) driving CPhar overexpression and knockdown were used in in-vivo experiments. Swim training was used to induce physiological cardiac hypertrophy in mice and ischemia reperfusion injury (IR/I) surgery was conducted to investigate the protective effects of CPhar in mice. To investigate the mechanisms of CPhar's function, we performed various analysis including RTqPCR, western blot, histology, cardiac function (by echocardiography), functional rescue experiments, mass spectrometry, in vitro RNA transcription, RNA pull down, RNA immunoprecipitation, chromatin immunoprecipitation assay, luciferase reporter assay, and coimmunoprecipitation assays.
Results: We screened the lncRNAs in contributing the modulation of exercise-induced cardiac growth via lncRNA microarray profiling and found that CPhar was increased with exercise and was necessary for exercise-induced physiological cardiac growth. Gain- and loss- of function of CPhar regulated the expression of proliferation markers, hypertrophy, and apoptosis in cultured neonatal mouse cardiomyocytes (NMCMs). Overexpression of CPhar prevented myocardial ischemia reperfusion injury and cardiac dysfunction in vivo . We identified DDX17 as a binding partner of CPhar in regulating CPhar downstream factor ATF7 by sequestering C/EBPβ.
Conclusions: Our study of this lncRNA CPhar provides new insights into the regulation of exercise-induced cardiac physiological growth, demonstrating the cardioprotective role of CPhar in the heart, as well as expanding our mechanistic understanding of lncRNA function.
Aim
Exercise is cardioprotective, though optimal interventions are unclear. We assessed duration dependent effects of exercise on myocardial ischemia-reperfusion (I-R) injury, kinase signaling and gene expression.
Methods
Responses to brief (2 day; 2EX), intermediate (7 and 14 day; 7EX and 14EX) and extended (28 day; 28EX) voluntary wheel running (VWR) were studied in male C57Bl/6 mice. Cardiac function, I-R tolerance and survival kinase signaling were assessed in perfused hearts.
Key findings
Mice progressively increased running distances and intensity, from 2.4 ± 0.2 km/day (0.55 ± 0.04 m/s) at 2-days to 10.6 ± 0.4 km/day (0.72 ± 0.06 m/s) after 28-days. Myocardial mass and contractility were modified at 14–28 days VWR. Cardioprotection was not ‘dose-dependent’, with I-R tolerance enhanced within 7 days and not further improved with greater VWR duration, volume or intensity. Protection was associated with AKT, ERK1/2 and GSK3β phosphorylation, with phospho-AMPK selectively enhanced with brief VWR. Gene expression was duration-dependent: 7 day VWR up-regulated glycolytic (Pfkm) and down-regulated maladaptive remodeling (Mmp2) genes; 28 day VWR up-regulated caveolar (Cav3), mitochondrial biogenesis (Ppargc1a, Sirt3) and titin (Ttn) genes. Interestingly, I-R tolerance in 2EX/2SED groups improved vs. groups subjected to longer sedentariness, suggesting transient protection on transition to housing with running wheels.
Significance
Cardioprotection is induced with as little as 7 days VWR, yet not enhanced with further or faster running. This protection is linked to survival kinase phospho-regulation (particularly AKT and ERK1/2), with glycolytic, mitochondrial, caveolar and myofibrillar gene changes potentially contributing. Intriguingly, environmental enrichment may also protect via similar kinase regulation.
Aims
To investigate the effects of aerobic exercise training on cardiomyocyte ultrastructure, oxidative stress, and activation of protein synthesis pathways in a model of cardiomyopathy induced by doxorubicin (Dox).
Main methods
Male Sprague Dawley rats were randomly assigned to Control (saline, sedentary), Dox/sedentary (DoxSed), or Dox/exercise (DoxEx) groups. Saline or Dox were injected i.p. for 10 days (1 mg/kg/d). Aerobic exercise training was performed for 9 wks (starting with drug administration) on a treadmill, 5 d/wk, 30 min/d at 60% of maximum velocity. After euthanasia, the left ventricle (LV) was dissected, and processed for microscopy or frozen for Western blot and kinetic measurement of antioxidant enzymes activity.
Key findings
Dox resulted in a mortality of 31.2% of sedentary animals, whilst all animals from both Control and DoxEx groups survived. DoxSed animals presented increased LV connective tissue deposition alongside with massive sarcomeric disorganization with dissolution of myofibrils and wavy Z-lines. There was an increase in oxidative damage and a reduction in the activation of both Akt and ERK pathways in LV from DoxSed compared to Control group. Aerobic training caused notable changes in myocardial structure with reduced fibrosis and preservation of myofibrils integrity and sarcomere organization. This was associated with reduced LV oxidative damage and increased activity of antioxidant enzymes, and an increase in the activation of PI3K-Akt pathway.
Significance
Aerobic exercise training was effective in preventing mortality caused by Dox and in preserving LV ultrastructure, partially via activation of the physiological protein synthesis pathway, PI3K-Akt, and reducing oxidative stress.
Background
Cardiopulmonary exercise testing (CPET) represents the gold standard to estimate peak oxygen consumption (VO2) noninvasively. To improve the analysis of the mechanisms behind effort intolerance, we examined whether exercise stress echocardiography measurements relate to directly measured peak VO2 during exercise in a large cohort of patients within the heart failure (HF) spectrum.
Methods
We performed a symptom-limited graded ramp bicycle CPET exercise stress echocardiography in 30 healthy controls and 357 patients: 113 at risk of developing HF (American College of Cardiology/American Heart Association stage A-B) and 244 in HF stage C with preserved (HFpEF, n = 101) or reduced ejection fraction (HFrEF, n = 143).
Results
Peak VO2 significantly decreased from controls (23, 21.7–29.7 mL/kg/minute; median, interquartile range) to stage A-B (18, 15.4-20.7 mL/kg/minute) and stage C (HFpEF: 13.6, 11.8-16.8 mL/kg/minute; HFrEF: 14.2, 10.7-17.5 mL/kg/minute). A regression model to predict peak VO2 revealed that peak left ventricular (LV) systolic annulus tissue velocity (S′), peak tricuspid annular plane systolic excursion/systolic pulmonary artery pressure (right ventricle-pulmonary artery coupling), and low-load left atrial (LA) reservoir strain/E/e’ (LA compliance) were independent predictors, in addition to peak heart rate, stroke volume, and workload (adjusted R² = 0.76, P < .0001). The model was successfully tested in subjects with atrial fibrillation (n = 49) and with (n = 224) and without (n = 163) beta-blockers (all P < .01). Peak S′ showed the highest accuracy in predicting peak VO2 < 10 mL/kg/minute (cut point ≤ 7.5 cm/sec, area under the curve = 0.92, P < .0001) and peak VO2 > 20 mL/kg/minute (cut point > 12.5 cm/sec, area under the curve = 0.84, P < .0001) in comparison with the other cardiac variables of the model (P < .05).
Conclusions
Peak VO2 is directly related to measures of LV systolic function, LA compliance, and right ventricle-pulmonary artery coupling, in addition to heart rate and stroke volume and independently of workload, age, and sex. The evaluation of cardiac mechanics may provide more insights into the causes of effort intolerance in subjects from HF stages A-C.
Background:
High-intensity interval training (HIIT) and aerobic training (AT) both improve cardiac function; however, their effects on cardiac function after myocardial infarction (MI) and the molecular mechanisms are unclear. In this study, HIIT, AT and sedentary (SED) interventions were performed for 4 weeks to compare the effects on cardiac function after MI and explore a more suitable approach for clinical application and the potential mechanisms.
Methods:
Twenty-four (24) male rats were randomly divided into a control group (CON), MI-sedentary group (MI-SED), MI-aerobic training group (MI-AT), and MI-high-intensity interval training group (MI-HIIT). After 4 weeks of intervention the exercise capacity, heart rate (HR), left ventricular end-diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), left ventricular ejection fraction (LVEF), AMP-activated protein kinase α1 (AMPKα1), cardiomyocyte morphology, and cardiac mitochondria were assessed.
Results:
After intervention: 1) exercise capacity in the MI-AT (49.08±3.141 m; p<0.001) and MI-HIIT (51.70±7.572 m; p<0.001) groups was significantly more increased than the MI-SED group; there was no significant difference between the MI-AT and MI-HIIT group (p=0.33). 2) LVEDD and LVESD in the MI-SED (p<0.01) and MI-HIIT (p<0.01) groups was significantly more increased than the CON group; the MI-AT group showed no significant difference in LVEDD and LVESD compared with the CON group; LVEF in the MI-AT (53.47±7.913%; p=0.03) and MI-HIIT (56.20±7.224%; p=0.006) groups was significantly more increased than the MI-SED group, and there was no statistical difference between the MI-AT and MI-HIIT groups. 3) AMPKα1 expression was significantly increased in the MI-AT (1.15±0.264; p=0.001) and MI-HIIT (1.04±0.238; p=0.003) groups and decreased in the MI-SED group (0.71±0.257; p<0.001) when compared with the CON group. 4) The MI-SED group exhibited sarcoplasmic dissolution and fibrous hyperplasia in the myocardium, cardiac mitochondrial damage and reduced mitochondrial numbers; the MI-HIIT group displayed swollen and vacuolated cardiac mitochondria with disrupted cristae; the MI-AT and MI-HIIT groups had significantly increased cardiac mitochondrial numbers than the MI-SED group; there was no statistical difference between the MI-AT and MI-HIIT groups.
Conclusions:
Aerobic training and HIIT for 4 weeks had similar cardioprotection and were superior to SED intervention. Both AT and HIIT improved cardiac function and exercise capacity by upregulating AMPKα1 expression. However, 4 weeks of intervention resulted in left ventricular dilation and cardiac myocardial mitochondrial injury in the MI-HIIT group.
Purpose:
To determine the effect of exercise training on preventing lipotoxic cardiomyopathy and investigate the role of the 3-hydroxy-3-methylglutaryl-CoA synthetase 2 (HMGCS2) and miR-344g-5p in cardiomyocytes.
Methods:
Male C57BL/6 mice fed a 60% high-fat diet (HFD) for 12 weeks, then began swimming exercise or remained sedentary for 8 weeks. Thereafter, cardiac function was assessed by echocardiography, and heart tissue and plasma were collected for further measurements. The molecular mechanism of exercise was investigated after treating Hmgcs2 siRNA in palmitate-induced neonatal mouse cardiomyocytes.
Results:
HFD induced myocardial hypertrophy and fibrosis, and reduced coronary reserve and cardiac function. HMGCS2 levels increased, but junctophilin-2 (JPH2) levels decreased in HFD mice hearts. Such effects were attenuated by swimming exercise. Mechanistically, silencing of Hmgcs2 prevented apoptosis and cleavage of caspase-3, and elevated expression of JPH2 in palmitate-stimulated cardiomyocytes. In addition, exercise promoted miR-344g-5p expression in HFD hearts. Overexpression of miR-344g-5p by chemical mimic reduced HMGCS2, apoptosis, cleavage of caspase-3, and elevated JPH2 expression in palmitate-induced cardiomyocytes.
Conclusion:
Our results suggest that exercise limits lipid metabolic disorder, cardiac hypertrophy and fibrosis, and aids in the prevention of lipotoxic cardiomyopathy. Exercise-mediated cardioprotection through up-regulating miR-344g-5p, which targets Hmgcs2 mRNA, prohibits HMGCS2 upregulation and thus against lipotoxicity.
The cardiac benefits of exercise have been recognized for centuries. Studies have undisputedly shown that regular exercise is beneficial for the cardiovascular system in young, old, healthy and diseased populations. For these reasons, physical activity has been recommended worldwide for cardiovascular disease prevention and treatment. Although the benefits of exercise are clear, understanding of the molecular triggers that orchestrate these effects remains incomplete and has been a topic of intense research in recent years. Here, we provide a comprehensive review of the cardiac effects of physical activity, beginning with a brief history of exercise in cardiovascular medicine and then discussing seminal work on the physiological effects of exercise in healthy, diseased and aged hearts. Later, we revisit pioneering work on the molecular mechanisms underlying the cardiac benefits of exercise, and we conclude with our view on the translational potential of this knowledge as a powerful platform for cardiovascular disease drug discovery. Moreira et al. discuss the physiological and molecular effects of exercise in healthy, diseased and aged hearts.
Rationale: Cardiac CITED4 is induced by exercise and is sufficient to cause physiological hypertrophy and mitigate adverse ventricular remodeling after ischemic injury. However, the role of endogenous CITED4 in response to physiological or pathological stress is unknown.
Objective: To investigate the role of CITED4 in murine models of exercise and pressure overload.
Methods and Results: We generated cardiomyocyte-specific CITED4 knockout mice (C4KO) and subjected them to an intensive swim exercise protocol as well as transverse aortic constriction (TAC). Echocardiography, western blotting, qPCR, immunohistochemistry, immunofluorescence, and transcriptional profiling for mRNA and miRNA expression were performed. Cellular crosstalk was investigated in vitro. CITED4 deletion in cardiomyocytes did not affect baseline cardiac size or function in young adult mice. C4KO mice developed modest cardiac dysfunction and dilation in response to exercise. After TAC, C4KOs developed severe heart failure with left ventricular dilation, impaired cardiomyocyte growth accompanied by reduced mammalian target of rapamycin (mTOR) activity and maladaptive cardiac remodeling with increased apoptosis, autophagy, and impaired mitochondrial signaling. Interstitial fibrosis was markedly increased in C4KO hearts after TAC. RNAseq revealed induction of a pro-fibrotic miRNA network. miR30d was decreased in C4KO hearts after TAC and mediated crosstalk between cardiomyocytes and fibroblasts to modulate fibrosis. miR30d inhibition was sufficient to increase cardiac dysfunction and fibrosis after TAC.
Conclusions: CITED4 protects against pathological cardiac remodeling by regulating mTOR activity and a network of miRNAs mediating cardiomyocyte to fibroblast crosstalk. Our findings highlight the importance of CITED4 in response to both physiological and pathological stimuli.
Whole body exercise tolerance is the consummate example of integrative physiological function among the metabolic, neuromuscular, cardiovascular, and respiratory systems. Depending on the animal selected, the energetic demands and flux through the oxygen transport system can increase two orders of magnitude from rest to maximal exercise. Thus, animal models in health and disease present the scientist with flexible, powerful, and, in some instances, purpose-built tools to explore the mechanistic bases for physiological function and help unveil the causes for pathological or age-related exercise intolerance. Elegant experimental designs and analyses of kinetic parameters and steady-state responses permit acute and chronic exercise paradigms to identify therapeutic targets for drug development in disease and also present the opportunity to test the efficacy of pharmacological and behavioral countermeasures during aging, for example. However, for this promise to be fully realized, the correct or optimal animal model must be selected in conjunction with reproducible tests of physiological function (e.g., exercise capacity and maximal oxygen uptake) that can be compared equitably across laboratories, clinics, and other proving grounds. Rigorously controlled animal exercise and training studies constitute the foundation of translational research. This review presents the most commonly selected animal models with guidelines for their use and obtaining reproducible results and, crucially, translates state-of-the-art techniques and procedures developed on humans to those animal models.
Listen to this article’s corresponding podcast at: https://ajpheart.podbean.com/e/guidelines-for-animal-exercise-and-training-protocols/ .
This study investigated the effects of exercise training on cardiac inflammatory and cardiac fibrotic pathways in female spontaneously hypertensive rats (SHR) which were divided into a sham-operated sedentary hypertensive group (SHR-S), a sedentary hypertensive ovariectomized group (SHR-O), hypertensive ovariectomized group with treadmill exercise training (SHR-OT, 60 min/day, 5 days/week) for 8 weeks. Normotensive female Wistar Kyoto rats (WKY) served as controls. SOD and CAT activities were significantly increased in the SHR-OT group, when compared with the SHR-S or SHR-O groups. The protein levels of ERα and ERβ became decreased in the SHR-O group, when compared with the WKY or SHR-S groups, but those were not changed in the SHR-OT group. The protein level of the angiotensin II type I receptor (AT 1 R) was increased in the SHR-S group, but did not further change those in the SHR-O group, whereas those were decreased in the SHR-OT group. The inflammatory-related protein levels of TNF-α, p-NFκB, COX-2, iNOS and IL-6, as well as the fibrotic-related protein levels of TGF-β, p-Smad2/3, CTGF, tPA, MMP9 and Collagen I were increased in the SHR-S group and increased further in the SHR-O group, whereas those were decreased in the SHR-OT group. The coexistence of hypertension and ovariectomy additively increased cardiac inflammatory and fibrotic pathways partially through hypertension-enhanced AT 1 R and ovariectomy-depressed estrogen receptors. Exercise training appeared to suppress hypertensive ovariectomized heart-induced inflammatory and fibrotic pathways possibly through decreasing AT 1 R, but not through estrogen receptors.
During aging, deterioration in cardiac structure and function leads to increased susceptibility to heart failure. The need for interventions to combat this age-related cardiac decline is becoming increasingly urgent as the elderly population continues to grow. Our understanding of cardiac aging, and aging in general, is limited. However, recent studies of age-related decline and its prevention through interventions like exercise have revealed novel pathological and cardioprotective pathways. In this review, we summarize recent findings concerning the molecular mechanisms of age-related heart failure and highlight exercise as a valuable experimental platform for the discovery of much-needed novel therapeutic targets in this chronic disease.
Objectives
The aim of this study was to evaluate the association between age and invasive cardiovascular hemodynamics during upright exercise among healthy adults.
Background
The marked age-related decline in maximal exercise oxygen uptake (peak VO2) may contribute to the high burden of heart failure among older individuals and their greater severity of exertional symptoms. However, the mechanisms underlying this decline are not well understood.
Methods
A total of 104 healthy community-dwelling volunteers age 20 to 76 years well screened for cardiovascular disease underwent exhaustive upright exercise with brachial and pulmonary artery catheters; radionuclide ventriculography; and expired gas analysis for the measurement of peak VO2, cardiac output, left ventricular stroke volume, end-diastolic volume, end-systolic volume, ejection fraction, pulmonary capillary wedge pressure, and arteriovenous oxygen difference.
Results
Over a 5.5-decade age range, there was a 40% decline in peak VO2 due primarily to reduced peak exercise cardiac output; peak arteriovenous oxygen difference was unaffected by age. The lower age-related exercise cardiac output was related to lower peak exercise heart rate and stroke volume. Aging was also associated with lower peak exercise ejection fraction, indicating reduced inotropic reserve. Peak exercise end-diastolic volume was lower with aging despite similar left ventricular filling pressure, suggesting age-related reduced diastolic compliance limiting the use of the Frank-Starling mechanism to compensate for reduced chronotropic and inotropic reserves. These age relationships were unaffected by sex.
Conclusions
The age-related decline in exercise capacity among healthy persons is due predominantly to cardiac mechanisms, including reduced chronotropic and inotropic reserve and possibly reduced Frank-Starling reserve. Peak exercise left ventricular filling pressure and arteriovenous oxygen difference are unchanged with healthy aging.
Pythons are important models of studies on postprandial metabolism because their physiological responses are exacerbated when digesting large prey. Prior studies of these animals have shown hypertrophy of the cardiac tissue 2 to 3 days after feeding, coinciding with the peak of the specific dynamic action (SDA), but the consequences of this remodeling in myocardial contractility have not been studied, which is the purpose of this work. Specimens of Python molurus were divided into two groups: a Digesting group (2 days after feeding, at the peak of SDA), and a Fasting group (28 days after feeding). When compared to the Fasting group, the Digesting group showed higher relative ventricular mass and calcium-handling protein expression such as sarcoplasmic reticulum Ca2+-ATPase (SERCA), phospholamban (PLB), and the Na+/Ca2+ exchanger (NCX). Digesting pythons also exhibited significant increases in the cardiac contraction force (Fc), rates of force development and relaxation, and cardiac pumping capacity. Therefore, the higher SERCA, PLB and NCX expression levels increased cytosolic Ca2+ transient amplitude, improving myofilament force. These changes are crucial to maintain cardiac output and a relatively high and continuous blood flow required by metabolic expenditure that occurs in postprandial animals.
Frailty syndrome increases the risk for disability and mortality, and is a major health concern amidst the geriatric shift in the population. High intensity interval training (HIIT), which couples bursts of vigorous activity interspersed with active recovery intervals, shows promise for the treatment of frailty. Here we compare and contrast five Fried physical phenotype and one deficit accumulation based mouse frailty assessment tools for identifying the impacts of HIIT on frailty and predicting functional capacity, underlying pathology, and survival in aged female mice. Our data reveal a 10-minute HIIT regimen administered 3-days-a-week for 8-weeks increased treadmill endurance, gait speed and maintained grip strength. One frailty tool identified a benefit of HIIT for frailty, but many were trending suggesting HIIT was beneficial for physical performance in these mice, but the 8-week timeframe may have been insufficient to induce frailty benefits. Finally, most frailty tools distinguished between surviving or non-surviving mice, whereas half correlated with functional capacity measured by nest building ability, and none correlated with underlying pathology. In summary, this study supports the ongoing development of mouse assessment tools as useful instruments for frailty research.
Post-myocardial infarction (MI) exercise has been employed to improve cardiac function. However, most studies have focused on endurance training (Et). Although Et has been reported to preserve cardiac function, evidence suggests that Et increases left ventricle (LV) interior dimensions as a result of albumin-induced plasma expansion. In contrast, strength training (St) induces concentric cardiac hypertrophy and improved cardiac function without causing ventricular dilation. Therefore, the purpose of this study was to investigate the effects of St on cardiac function and remodeling in rats with MI. MI was surgically induced in 7-week-old rats via ligation of the coronary artery. Survivors were assigned to two experimental groups, MI-Sed (No exercise; n = 9), MI-St (St; n = 10), with a Sham group (no MI, no St; n = 9). MI-St rats began training 1-week post-MI by climbing a ladder with weights for 10 weeks. Echocardiographic measurements were performed prior to, and following exercise training, while in vivo LV hemodynamic analysis was conducted at the end of the experimental period. Our data revealed that St induced shortening of the LV end-diastolic dimension in the MI-St group compared with the MI-Sed group (P < 0.05). The peak velocities of contraction (+ dP/dt max) and relaxation (− dP/dt max) were significantly greater in the MI-St group than the MI-Sed group (P < 0.05). These training effects contributed to the improved fractional shortening (%FS). Our results demonstrate that St may be beneficial for post-MI by attenuating LV dilation and concomitant cardiac dysfunction associated with MI.
Activin type II receptor (ActRII) ligands have been implicated in muscle wasting in aging and disease. However, the role of these ligands and ActRII signaling in the heart remains unclear. Here, we investigated this catabolic pathway in human aging and heart failure (HF) using circulating follistatin-like 3 (FSTL3) as a potential indicator of systemic ActRII activity. FSTL3 is a downstream regulator of ActRII signaling, whose expression is up-regulated by the major ActRII ligands, activin A, circulating growth differentiation factor-8 (GDF8), and GDF11. In humans, we found that circulating FSTL3 increased with aging, frailty, and HF severity, correlating with an increase in circulating activins. In mice, increasing circulating activin A increased cardiac ActRII signaling and FSTL3 expression, as well as impaired cardiac function. Conversely, ActRII blockade with either clinical-stage inhibitors or genetic ablation reduced cardiac ActRII signaling while restoring or preserving cardiac function in multiple models of HF induced by aging, sarcomere mutation, or pressure overload. Using unbiased RNA sequencing, we show that activin A, GDF8, and GDF11 all induce a similar pathologic profile associated with up-regulation of the proteasome pathway in mammalian cardiomyocytes. The E3 ubiquitin ligase, Smurf1, was identified as a key downstream effector of activin-mediated ActRII signaling, which increased proteasome-dependent degradation of sarcoplasmic reticulum Ca ²⁺ ATPase (SERCA2a), a critical determinant of cardiomyocyte function. Together, our findings suggest that increased activin/ActRII signaling links aging and HF pathobiology and that targeted inhibition of this catabolic pathway holds promise as a therapeutic strategy for multiple forms of HF.
Age-related fibrosis is attenuated by aerobic exercise; however, little is known concerning the underlying molecular mechanism. To address this question, aged rats were given moderate-intensity exercise for 12 weeks. After exercise in aged rats, hydrogen sulfide (H2S) levels in plasma and heart increased 39.8% and 90.9%, respectively. Exercise upregulated expression of cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST) in heart of aged rats. Furthermore, aged rats were given moderate-intensity exercise for 12 weeks or treated with NaHS (intraperitoneal injection of 0.1 ml/kg/day of 0.28 mol/l NaHS). After exercise in aged rats, Masson-trichrome staining area decreased 34.8% and myocardial hydroxyproline levels decreased 29.6%. Exercise downregulated expression of collagen-I and α-SMA in heart of aged rats. Exercise in aged rats reduced malondialdehyde levels in plasma and heart and 3-nitrotyrosine in heart. Exercise in aged rats reduced mRNA and protein expression of CHOP, GRP78, and XBP1. Exercise also reduced mRNA and protein expression of IL-6 and MCP-1 and suppressed activation of JNK in aging heart. Similar effects were demonstrated in aged rats treated with NaHS. Collectively, exercise restored bioavailability of hydrogen sulfide in the heart of aged rats, which partly explained the benefits of exercise against myocardial fibrosis of aged population.
Exercise training effects on the contractility of aged myocardium have been investigated for more than 20 years, but the data are still unclear. This study evaluated the hypothesis that a swimming training (ST) may improve myocardial inotropism in older rats. Male Wistar rats aged 4 (young)-and 21 (old)-months-old were divided into young untrained (YNT), old untrained (ONT), and old trained (OTR; 6 weeks of ST) groups. Echocardiography and hemodynamic were employed to assess left ventricular morphology and function. Myocardial mechanics was evaluated on papillary muscles. Histological and immunoblotting were carried out to evaluate fibrosis and proteins that modulate the myocardial function. We found that older rats did not show cardiac dysfunction, but ONT group showed lower physical performance during a swimming test (YNT:5±2; ONT:-16±0.4; OTR:51±3; Δ%). Moreover, ONT group showed worse myocardial inotropism, in which it was reversed by ST (Peak developed tension: YNT:6,2±0.7; ONT:3.9±0.3; OTR:6.9±0.9; g/mm²). The ST was associated with preserved collagen content (YNT:0.38±0.05; ONT:0.78±0.12; OTR:0.34±0.09; %). Exercise partially mitigated the effects of aging on intracellular Ca²⁺⁻regulating protein (e.g., L-Ca2+ channel and phospholamban) and β-isoform of myosin. Thus, we propose that these molecular alterations together with inhibition of collagen increase contribute to improved myocardial performance in older rats.
Aims:
Exercise is beneficial in obesity, however, the debate about the value of high-intensity interval training (HIIT) vs. moderate-intensity continuous training (MICT) has been long lasting. Therefore, here we have compared the possible beneficial effects of two different exercise training regimes in a mouse model of diet-induced obesity (DIO).
Materials and methods:
Following 7wk. on high fat diet (HFD), ten-week-old male ICR mice (n=30) were assigned to HIIT, distance-matched MICT or remained sedentary for the next 8 constitutive weeks while maintaining the dietary treatments. Age-matched sedentary mice with standard diet were used as a control (n=10). Exercise was performed on a motorized treadmill for 5days a week.
Key findings:
Both modes of exercise ameliorated adiposity and related metabolic dysfunction induced by HFD and sedentary lifestyle, while mice following HIIT exhibited significantly lower body weight, percentage of fat mass and smaller adipocyte size. HIIT was more favorable in preventing liver lipid accumulation by restoring mRNA levels of genes involved in hepatic lipogenesis (SREBP1, ACC1, FAS) and β-oxidation (PPARα, CPT1a, HAD). In addition, HIIT was more efficient in mitigating adipose tissue inflammation and insulin insensitivity, partly dependent on abrogating phosphorylation of JNK/IRS1 (Ser307) pathway. Moreover, only HIIT led to pronounced beige adipocyte recruitment in inguinal subcutaneous adipose tissue.
Significance:
We conclude that HIIT contribute a more favorable regulation of metabolic dysfunctions in DIO mice compared with MICT.
Objective
Chronic heart failure (CHF) is related with exercise intolerance and impaired nitric oxide (NO) production, which can lead to several functional capacity alterations. Considering the possible superiority of aerobic interval training compared to continuous training and the capacity of L-arginine to restore the NO pathway, the aim of the present study was to investigate whether these treatments are beneficial to exercise capacity, muscle mass preservation and hemodynamic, inflammatory and oxidative stress parameters in CHF rats.
Methods
Thirty-eight male Wistar rats post 6 weeks of myocardial infarction (MI) surgery were randomly assigned into 6 CHF groups: sedentary (SED, n = 6); SED+Arg (n = 7); ACT (n = 8); ACT+Arg (n = 5); AIT (n = 7); AIT+Arg (n = 5). Exercise test capacity (ETC) was performed pre and post 8 weeks of intervention. Supplemented rats received Arg (1g/kg) by oral gavage (7x/ week). Exercise training was performed on a rat treadmill (5x/ week). Hemodynamic variables, tissue collection, congestion, inflammatory cytokines, and oxidative parameters were evaluated at the end of protocols.
Results
All trained groups showed a superior exercise capacity compared to SED groups on the post-intervention test (p<0.0001). Pulmonary congestion was attenuated in AIT and AIT+Arg compared with the SED group (p<0.05). Left ventricular end-diastolic pressure (LVEDP) was lower in ACT+Arg, AIT, and AIT+Arg groups than SED group (p<0.05). Association of AIT with Arg supplementation was able to improve hemodynamic responses (left ventricular systolic pressure (LVSP), systolic blood pressure (SBP), +dP/dtmax, and -dP/dtmax (p<0.05), likewise, decrease muscular and renal lipid peroxidation and tumor necrosis factor (TNF)-α, and increase interleukin (IL)-10/TNF-α plasmatic levels (p<0.01). Groups that associated aerobic exercise with Arg supplementation (ACT+Arg and AIT+Arg) revealed higher gastrocnemius mass compared to the SED group (p<0.01).
Conclusions
Both aerobic training protocols were capable to improve aerobic capacity, and the association with Arg supplementation was important to attenuate muscle loss. Moreover, interval training associated with Arg supplementation elicits greater improvements in hemodynamic parameters, contributing to reduction in pulmonary congestion, and demonstrated particular responses in the inflammatory profile and in the antioxidant status.