Physiological Reports

The use of genetically diverse mouse models offers a more accurate reflection of human genetic variability, improving the translatability of findings to heterogeneous human populations. This approach is particularly valuable in understanding diverse immune responses to disease by environmental exposures. This study investigates the inflammatory responses to acute exposures to mainstream cigarette smoke (CS) and environmental tobacco smoke (ETS) in two genetically diverse mouse strains, CC002/UncJ (UNC) & Diversity Outbred (J:DO). The UM‐HET3 (HET3) mouse strain, typically used in aging intervention studies, has also been used to evaluate the translatability of this model for age‐associated pathologies. The study involves a comprehensive approach, including BALF cytokine analysis, evaluation of lung tissue architecture, assessment of macrophages and its associated proteins (MMP9 & MMP12) abundance. Several cytokines/chemokines were found to be upregulated across three strains. Notably, the UNC strain exclusively showed upregulation of TNF‐α, IL‐17A, and IL‐13, whereas the J:DO showed an upregulation in KC. The number of alveolar macrophages in the lungs of UNC mice was very low at baseline compared to other strains studied in this study, which is indicative of some inherent shift in the pulmonary immune profiles of these inbred mice. In contrast, the J:DO strain, characterized by genetic outbreeding, showed a much more robust lung macrophage response comparable to C57BL/6J. The findings provide valuable insight into how genetic diversity affects immune responses in response to acute CS/ETS exposure, with implications for understanding diverse human responses to environmental stressors in studying lung pathophysiology.

The twin testosterone transfer (TTT) hypothesis posits that females with male co‐twins (opposite‐sex, OS) might develop male‐typical traits due to higher prenatal testosterone exposure. This study explored whether females of OS have lower 2D:4D digit ratios and higher testosterone levels compared to females of same‐sex (SS) twin pairs. Conducted in Tamale from January to December 2022, the study included 40 participants aged 18–27 years: 10 males of OS, 10 females of OS, and 20 females of SS twin pairs. Digit ratios (2D:4D) and serum testosterone levels were measured using computer‐assisted analysis and ELISA, respectively. Results showed no significant differences in 2D:4D ratios between females of OS and SS twin pairs for either the right hand (0.960 ± 0.049 vs. 0.955 ± 0.042; p = 0.766) or the left hand (0.966 ± 0.048 vs. 0.968 ± 0.047; p = 0.908). Serum testosterone levels were lower in females of OS than females of SS twin pairs (0.4 ± 0.1 vs. 0.67 ± 0.34 nmol/L; p = 0.013), but this result was not significant after multiple testing corrections (p > 0.050). The findings indicate that the TTT hypothesis may not apply, or its effects on digit ratios and testosterone levels in females of OS twin pairs are weak and not statistically significant. Further studies involving larger samples are however, recommended.

Time‐restricted feeding (TRF) and aerobic exercise are lifestyle interventions to prevent or manage different metabolic diseases. How these interventions interact, including the impact of meal timing, is not well understood. The aim of this study was to examine the influence of TRF on fat oxidation during exercise, whereby participants performed an 8‐week fatmax‐training program either in the fasted state or after a carbohydrate‐based snack. 36 participants were randomized into three groups. (1) Training sessions were performed in the fasted state; (2) Training sessions were performed after consuming a standardized carbohydrate‐based snack; (3) Exercise training with an ad libitum diet as a control group. Pre‐ and post‐tests included anthropometric measurements and a fatmax‐cycle‐ergometry protocol to measure substrate oxidation. Data were analyzed as workload‐matched and maximal fat oxidation using a series of mixed ANOVAs. Workload‐matched (p = 0.038) and maximal (p < 0.001) fat oxidation improved in all groups. No significant group × time interactions were found in substrate utilization. Time had a significant effect on body weight (p = 0.011), fat mass (p < 0.001), and muscle mass (p < 0.001). Results suggest that fatmax exercise training leads to improvements in fat oxidative capacity independent of fed or fasted state.

Melatonin is a multifunctional biomolecule with demonstrated stimulatory, inhibitory, and antioxidant effects, including both receptor‐mediated and receptor‐independent mechanisms of action. One of its more perplexing effects is the disruption of regeneration in planaria. Head regeneration in planaria is a remarkable phenomenon in which stem cells (neoblasts) migrate to the wound site, proliferate, then differentiate into all functional tissue types within days of injury. We investigated how both the timing and duration of melatonin exposure affect head regeneration in the planaria Phagocata gracilis (Haldeman). Our results demonstrate that P. gracilis is capable of recovery from the melatonin‐induced delay of regeneration and reveal the time required to recover to control levels. Further, we found evidence of regenerative stage‐specific responses to discontinuous melatonin exposure, including non‐inhibitory effects. Further exploration of melatonin's effects on regeneration can be targeted to specific regenerative processes, and the possibility of multiple mechanisms of action should be recognized.

Both resistance training (RT) and long‐duration, high‐intensity stretching induce muscular adaptations; however, it is unknown whether the modalities are complementary or redundant, particularly in well‐trained individuals. A case‐study was conducted on a competitive bodybuilder implementing long‐duration, high‐intensity stretching of the plantar flexors (60 min 6x/week for 12 weeks) in conjunction with their habitual RT. Ultrasound muscle architecture (muscle thickness [MT], fascicle length [FL], and pennation angle [PA]) measurements were collected at multiple sites at four weekly baseline sessions, six (mid) and 12 (post1) weeks following the commencement of the intervention, and a week after the intervention (post2) while isometric strength and range of motion (RoM) were obtained once at baseline, mid, post1, and post2. 2SD band plots were constructed to determine meaningful changes in MT, FL, and PA from the four baseline measures while percentage and absolute change across each timepoint were calculated for all variables. From baseline to post 1, RoM, strength, and MT increased 25.9%, 11.4%, and 7.4%–23.4%, respectively, while four MT and two PA sites exceeded the threshold for meaningful change. The combined stretching and RT protocols resulted in flexibility, strength, and MT adaptations; however, findings should be generalized with caution given the case‐study nature of our investigation.

Police officers are exposed to high levels of stress. Serving on Special Weapons and Tactics (SWAT) teams is a highly demanding duty that may further increase levels of stress in police personnel. This stress may accumulate, thereby increasing allostatic load. As such, holistic stress measures may be valuable for quantifying multifactorial stress accumulation in SWAT personnel. Heart rate variability (HRV) is one field‐deployable measure that may be suitable in this context. However, with logistical challenges present in this population, determining if 30 s; rather than more the typical 5‐min ECG data collection, provides sufficient reliability may be beneficial for reducing the logistical barrier to adoption of HRV monitoring in SWAT personnel. This study compared 30‐s to 5‐min HRV analyses of ECG data obtained from 15 male SWAT personnel. Findings demonstrated good (ICC >0.8) reliability only in the VLF, HF, SD1, and SD2 HRV domains. The VLF and SD2 measures may be erroneous, as 5‐min may still insufficiently characterize these measures. However, this study confirms the robust quality of nonlinear HRV analysis, as the SD1 value demonstrated the highest ICC reported here (0.902). Therefore, while 5‐min ECGs may still preferable, the 30‐s measure may still be viable for organizations considering HRV assessment.

Polycystic kidney diseases (PKD) are genetic disorders which disrupt kidney architecture and function. Autosomal recessive PKD (ARPKD) is a rare form of PKD, caused by mutations in PKHD1, and clinically more severe than the more common autosomal dominant PKD (ADPKD). Prior studies have implicated Hedgehog (Hh) signaling in ADPKD, with increased levels of Hh components in experimental ADPKD and reduced cystogenesis following pharmacological Hh inhibition. In contrast, the role of the Hh pathway in ARPKD is poorly understood. We hypothesized that Hh pathway activity would be elevated during ARPKD pathogenesis, and its modulation may slow disease progression. We utilized Cpk mice which phenocopy ARPKD and generated a PKHD1‐mutant spheroid model in human collecting ducts. Significantly elevated levels of the Hh transcriptional effector Gli3 were found in Cpk mice, a finding replicated in PKHD1‐mutant spheroids. In Cpk mice, total GLI3 and GLI3 repressor protein levels were also increased. Reduction of increased Gli3 levels via heterozygous genetic deletion in Cpk mice did not affect cyst formation. Additionally, lowering GLI3 transcripts to wildtype levels did not influence PKHD1‐mutant spheroid size. Collectively, these data suggest attenuation of elevated Gli3 does not modulate murine and human models of ARPKD.

Exercise counters many adverse health effects of consuming a high‐fat diet (HFD). However, complex molecular changes that occur in skeletal muscle in response to exercising while consuming a HFD are not yet known. We investigated the interplay between diverse exercise regimes and HFD consumption on the adaptation of skeletal muscle transcriptome. C57BL/6 male mice were randomized into five groups—one sedentary control group and four exercise groups. The exercise groups consisted of an unrestricted running group (8.3 km/day) and three groups that were restricted to 75%, 50%, or 25% of unrestricted running (6.3, 4.2, and 2.1 km/day, respectively). Total RNA was extracted from frozen gastrocnemius muscle for transcriptome analyses. DEG counts were 1347, 1823, 1103, and 1107 and there were 107, 169, 67, and 89 unique genes present in the HFD‐25%, HFD‐50%, HFD‐75%, and HFD‐U, respectively. Comparing exercise groups, we found that exercising at 50% resulted in the most differentially expressed transcripts with the MAPK and PPAR signaling pathways enriched in down‐ and up‐regulated genes, respectively. These results demonstrate that running distance impacts the adaptation of the skeletal muscle transcriptome to exercise and suggest that middle‐distance running may provide the greatest protection against high‐fat diet‐induced stress coupled with exercise.

The effects of social isolation (SI) during middle age remain unclear, so we tested the hypothesis that SI would lead to an increase in impulsive choice (IC), anxiety‐like behavior, and metabolic dysfunction in middle‐aged rats. Male and female rats were housed individually or in groups of four with same‐sex housing mates at 11 months of age. Two months later, IC behavior was assessed using a delay‐discounting task and anxiety‐like behavior through a novelty‐suppressed feeding (NSF) task. Lastly, glucose tolerance and insulin sensitivity following exposure to a high‐fat diet were assessed using an oral glucose tolerance test (OGTT) and an insulin tolerance test (ITT). The results showed that socially isolated rats displayed more IC behavior than did group‐housed rats of both sexes. However, no significant effect of housing was evident in the NSF task, OGTT, or ITT. Male rats had a higher plasma insulin concentration and insulin resistance index compared to females. Our findings demonstrate that SI in middle age is sufficient to increase IC behavior and highlight inherent sex‐specific differences in metabolic profiles. These findings underscore the importance of investigating mechanisms that underlie the effects of social isolation during different stages of life.

Type 2 diabetes (T2D) is a common metabolic disorder in which only 25% of patients meet management targets. While the primary care setting is positioned to provide lifestyle management education, studies are lacking which integrate behavior interventions in this setting utilizing clinic staff. Thus, we evaluated a 90‐day lifestyle intervention for management of glycemia at a family practice clinic administered by clinic medical assistants. Twenty patients with non‐insulin‐dependent T2D completed a 90‐day intervention driven by patient choices of nutrition and physical activity. Medical assistants were trained by members of the study team and administered the intervention under nurse practitioner supervision. HbA1c trended toward significant reduction 8.59 ± 0.9% to 8.15 ± 1.2% (p = 0.051, 95% CI: −0.88 to 0.003). Modest reductions were observed for waist circumference (115.5 ± 12.6 vs. 112.5 ± 15.2 cm; p = 0.014, 95% CI: −5.66 to −0.26), body weight (97.7 ± 21.9 vs. 95.6 ± 23.9 kg; p = 0.016. 95% CI: −3.84 to −0.31), and BMI (33.7 ± 7.2 vs. 32.8 ± 7.5 kg/m²; p = 0.028, 95% CI: −1.29 to −0.12). This 90‐day, patient choice‐intervention was successful at lowering HbA1c in patients with T2D. Our study is limited by a lack of control group, and results should be interpreted as such. These data have implications for team‐based care models in clinic settings to improve health outcomes in patients with T2D.

While autonomic dysregulation and repolarization abnormalities are observed in subarachnoid hemorrhage (SAH), their relationship remains unclear. We aimed to measure skin sympathetic nerve activity (SKNA), a novel method to estimate stellate ganglion nerve activity, and investigate its association with electrocardiogram (ECG) alterations after SAH. We recorded a total of 179 SKNA data from SAH patients at three distinct phases and compared them with 20 data from controls. Compared with control data, in the acute phase data (days 1–3 of SAH), T peak‐to‐end (Tp‐e) interval was significantly prolonged (81 [interquartile range {IQR}: 71–93] vs. 58 [IQR: 54–64] ms, p < 0.001), non‐burst amplitude of SKNA was significantly increased (2.4 [IQR: 1.3–4.1] vs. 0.7 [IQR: 0.5–1.7] μV, p < 0.001), and the ratio of low frequency to high frequency (HF) was significantly decreased (0.8 [IQR: 0.5–1.1] vs. 1.1 [IQR: 0.7–1.3], p = 0.028). Linear mixed model revealed a relationship between Tp‐e interval and SKNA. Although these abnormalities gradually normalized, delayed cerebral ischemia episodes were associated with increased HF oscillation. Transient sympathetic dysregulation contributes to repolarization impairment after SAH. SKNA may have the potential to monitor adverse outcomes.

Maximal oxygen uptake (VO2max) in healthy subjects is primarily limited by systemic oxygen delivery. In chronic kidney disease (CKD), VO2max is potentially reduced by both central and peripheral factors. We aimed to investigate the effect on VO2peak of adding arm exercise to leg exercise. Ten individuals with CKD stages 3–5 and 10 healthy controls, matched for age, sex, body size, and physical activity level, were included. Subjects performed two maximal exercise tests, one with legs only (L exercise) and one test where arm exercise was added to leg exercise (LA exercise). The increase in VO2peak, when comparing LA exercise with L exercise, was significantly higher in CKD (0.20 ± 0.18 L/min or 2.31 ± 1.78 mL/(kg·min)) than in controls (0.019 ± 0.12 L/min or 0.26 ± 1.62 mL/(kg·min); p = 0.02 and 0.01, respectively). The decrease in peak leg workload, when comparing L exercise with LA exercise, was larger in controls than in CKD, in absolute terms (p = 0.002) and relative to body weight (p = 0.01). VO2max in individuals with CKD is dependent on the active muscle mass, supporting a peripheral limitation to VO2max in CKD. By contrast, the control group appeared to have a more central limitation to VO2max.

Given the growing concern over the impact of brain health in individuals with overweight, understanding how mental exertion (ME) during exercise affects substrate oxidation and cardiorespiratory outcomes is crucial. This study examines how ME impacts these outcomes during an incremental exercise test in adults with overweight. Seventeen adults who were overweight completed an incremental exercise test on a cycle ergometer two times, with and without the Stroop task. Energy expenditure (EE), carbohydrate and fat oxidation, maximum heart rate (HRmax), maximal oxygen uptake (VO2max), maximum fat oxidation (MFO), and the intensity of exercise that elicited MFO (Fatmax) are measured by indirect calorimetry. ME did not change the EE, carbohydrate, and fat oxidation at any stages of the incremental test. However, ME resulted in significantly lower HRmax, VO2max, and MFO (p < 0.01) and increased NASA‐TLX scores but showed no change in Fatmax. These results show ME decreases the value of HRmax, VO2max, and MFO during the incremental exercise test. Due to the increased mental workload demonstrated by the NASA‐TLX test, adults with overweight are unable to complete the test to the same extent as they did in the test without ME according to maximal levels in this study.

Transient receptor potential (TRP) channels with temperature sensitivities (thermo‐TRPs) are involved in various physiological processes. Thermo‐TRPs that detect temperature changes in peripheral sensory neurons possess indispensable functions in thermosensation, eliciting defensive behavior against noxious temperatures and driving autonomic/behavioral thermoregulatory responses to maintain body temperature in mammals. Moreover, most thermo‐TRPs are functionally expressed in cells and tissues where the temperature is maintained at a constant core body temperature. To perform physiological functions, the activity of each thermo‐TRP channel must be regulated by endogenous mechanisms at body temperature. Dysregulation of this process can lead to various diseases. This review highlights the endogenous factors regulating thermo‐TRP activity and physiological functions at constant core body temperature.

Cisplatin is a widely used anticancer drug, but its accumulation in renal tubular epithelial cells (TECs) can cause acute kidney injury. Phosphoseryl‐tRNA kinase (PSTK) is an intermediate product produced under oxidative stress conditions. This study aimed to elucidate whether PSTK could protect TECs and its possible mechanisms. We found that PSTK levels decreased after cisplatin treatment, but PSTK overexpression using lentivirus vectors protected TEC viability. Overexpression of PSTK increased selenoprotein concentrations and reduced intracellular ROS levels. Additionally, PSTK overexpression inhibited the BAX/BCL2/Caspase 3 pathway after cisplatin stimulation, suggesting its potential role in preventing cell apoptosis. Taken together, this study suggests that PSTK could protect TEC viability from cisplatin‐induced injury, possibly by inhibiting mitochondrial apoptosis. The study is significant for developing therapeutic strategies that could manipulate PSTK to delay AKI progression.

I see, I forget, I read aloud, I remember, and when I do read purposefully by writing it, I do not forget it.” This phenomenon is known as “interoception” and refers to the sensing and interpretation of internal body signals, allowing the brain to communicate with various body systems. Dysfunction in interoception is associated with cardiovascular disorders. We delve into the concept of interoception and its impact on heart failure (HF) by reviewing and exploring neural mechanisms underlying interoceptive processing. Furthermore, we review the potential of artificial intelligence (AI) in diagnosis, biomarker development, and HF treatment. In the context of HF, AI algorithms can analyze and interpret complex interoceptive data, providing valuable insights for diagnosis and treatment. These algorithms can identify patterns of disease markers that can contribute to early detection and diagnosis, enabling timely intervention and improved outcomes. These biomarkers hold significant potential in improving the precision/efficacy of HF. Additionally, AI‐powered technologies offer promising avenues for treatment. By leveraging patient data, AI can personalize therapeutic interventions. AI‐driven technologies such as remote monitoring devices and wearable sensors enable the monitoring of patients' health. By harnessing the power of AI, we should aim to advance the diagnosis and treatment strategies for HF. This review explores the potential of AI in diagnosing, developing biomarkers, and managing HF.

This study investigated sex differences in the development of pulmonary edema and exercise‐induced arterial hypoxemia (EIAH) in well‐trained endurance athletes during near‐maximal exercise in a real‐world setting. Twenty participants (10M vs. 10F; V̇O2peak: 69.3 (8.8) vs. 50.7 (4.1) ml∙kg⁻¹∙min⁻¹) underwent a maximal incremental treadmill test (visit 1) and a time trial on a steep trail (~2.5 km, ~800 m elevation gain) in North Vancouver (visit 2). Pulmonary edema was evaluated using handheld lung ultrasound ~10–15 min post‐exercise and oxygen saturation (SpO2) was monitored using finger pulse oximetry. Males completed the time trial significantly faster than females (M: 31.5 (6.5) vs. F: 40.4 (7.5) min, p = 0.006), while females sustained a higher percentage of their visit 1 heart rate (M: 94 (1) vs. F: 96 (1) %max, p = 0.02). All participants developed EIAH, with no sex differences in end‐exercise SpO2 (M: 89 (4) % vs. F: 90 (3) %, respectively, p = 0.35). There was no evidence of pulmonary edema, assessed through ultrasound b‐line scores, with no differences between sexes (M: 0.3 (1.0) vs. F: 0.5 (1.5), respectively, p = 0.60). Pulmonary edema is an unlikely contributor to EIAH in endurance athletes performing near‐maximal time trial exercise in a real‐world setting.

To assess the impact of thoracic load carriage on the physiological response to exercise in hypoxia. Healthy males (n = 12) completed 3 trials consisting of 45 min walking in the following conditions: (1) unloaded normoxia (UN; FIO2:20.93%); (2) unloaded hypoxia (UH; FIO2:~13.0%); and (3) loaded hypoxia (LH; 29.5 kg; FIO2:~13.0%). Intensity was matched for absolute VO2 (2.0 ± 0.2 L·min⁻¹) across conditions and relative VO2 (64.0 ± 2.6 %VO2max) across hypoxic conditions. With LH versus UH, there were increases in breathing frequency (5–11 breaths·min⁻¹; p < 0.05) and decreases in tidal volume (10%–18%; p < 0.05) throughout exercise due to reductions in end inspiratory lung volumes (p < 0.05). Consequently, deadspace (11%–23%; p < 0.05) and minute ventilation (7%–11%; p < 0.05) were increased starting at 20 and 30 min, respectively. In addition, LH increased perceived exertion/dyspnea and induced inspiratory (~12%; p < 0.05 vs. UN) and expiratory (~10%; p < 0.05 vs. pre‐exercise) respiratory muscle fatigue. Expiratory flow limitation was present in 50% of subjects during LH. Cardiac output and muscle oxygenation were maintained during LH despite reduced stroke volume (6%–8%; p < 0.05). Finally, cerebral oxygenated/total hemoglobin were elevated in the LH condition versus UH starting at 15 min (p < 0.05). Thoracic load carriage increases physiological strain and interferes with the compensatory response to hypoxic exposure.

While total RNA concentrations putatively represent ribosome content, there is a need to homologize various quantification approaches. Thus, total RNA concentrations ([RNA]) provided through UV–Vis spectroscopy (UV), fluorometry‐only (Fluor), and fluorometry‐based microfluidic chip electrophoresis (MFGE) were examined in C2C12 myotubes and mouse skeletal muscle to determine if values aligned with [18S + 28S rRNA] (i.e., criterion ribosome metric). A novel antibody cocktail (termed RiboAb) was also tested and compared to [18S + 28S rRNA] in these models. In myotubes, 24‐h IGF‐1 treatments increased [18S + 28S rRNA] (~2.0‐fold) and [RNA] based on UV (~1.9‐fold), Fluor (~2.3 fold), and MFGE (~2.1‐fold). In C57BL/6 mice, 10 days of mechanical overload (MOV) elevated plantaris [18S + 28S rRNA] (~1.7‐fold) and [RNA] according to UV (~1.5‐fold), Fluor (~1.6‐fold), and MFGE (~1.8‐fold). Myotube and mouse plantaris RiboAb levels were significantly higher with IGF‐1 treatments and MOV, respectively, versus controls (1.3‐fold and 1.7‐fold, respectively), and values correlated with [18S + 28S rRNA] (r = 0.637 and r = 0.853, respectively, p ≤ 0.005). UV, Fluor, and MFGE [RNA] are seemingly valid surrogates of cell/tissue ribosome content, although each method has advantages (e.g., ease of use) and disadvantages (e.g., magnitudes of bias) discussed herein. Finally, the RiboAb cocktail may also represent ribosome content, although this should be further explored in other models.

The effect of acetazolamide on regional brain tissue oxygenation in patients with acute brain injury (ABI) is unknown. We studied adult patients with ABI who received acetazolamide as per the treating physician's decision and had ICP and brain oxygen pressure (PbtO2) monitoring. Baseline measurements of ICP, cerebral perfusion pressure (CPP), and PbtO2 were taken before administering acetazolamide; subsequent measurements were recorded every 5 min for a total of 20 min. Mean cerebral blood velocities (FVm) and pulsatility index (PI) were measured using transcranial color‐coded duplex (TCCD) sonography at baseline and after 20 min. Fourteen patients with subarachnoid hemorrhage (n = 6), traumatic brain injury (n = 7), and intracranial hemorrhage (n = 1) were included. Following administration of acetazolamide, ICP showed a significant increase within 20 min (p < 0.001), with no significant change in CPP (p = 0.08). PbtO2 demonstrated a significant increase (p < 0.001), with a noticeable change observed at 10 min after acetazolamide administration (15 [14–17] vs. 28 [26–30] mmHg). Additionally, FVm exhibited a significant increase (p < 0.001), and PI showed a reduction (p < 0.001). Administration of acetazolamide in ABI patients resulted in a significant increase in brain oxygenation, associated with a rise in ICP and FVm, suggesting increased cerebral volume and vasodilation.

MicroRNAs (miRNAs) are small, noncoding RNAs that play a critical role in regulating gene expression post‐transcriptionally. They are involved in various developmental and physiological processes, and their dysregulation is linked to various diseases. Skeletal muscle‐specific miRNAs, including miR‐1, play a crucial role in the development and maintenance of skeletal muscle. It has been demonstrated that the expression of miR‐1 decreases by approximately 50% in response to hypertrophic stimuli, suggesting its potential involvement in muscle hypertrophy. In our study, we hypothesize that reduction of miR‐1 levels is necessary for skeletal muscle growth due to its interaction to essential pro‐growth genes. Promoting a smaller reduction of miR‐1 levels, we observed a blunted hypertrophic response in mice undergoing a murine model of muscle hypertrophy. In addition, our results suggest that miR‐1 inhibits the expression of Itm2a, a membrane‐related protein, as potential miR‐1‐related candidate for skeletal muscle hypertrophy. While the exact mechanism in muscle hypertrophy has not been identified, our results suggest that miR‐1‐regulated membrane proteins are important for skeletal muscle hypertrophy.

Inflammation and a metabolic shift from oxidative metabolism to glycolysis are common in the ischemic heart, the latter partly controlled by pyruvate kinase (muscle, PKM). We previously identified alternative splicing promoting the PKM2 isoform after myocardial infarction (MI). We examined the role of PKM2 physiological upregulation after MI, modeled by ligation of the left anterior descending coronary artery, using global PKM2 knockout (PKM2−/−) mice. Echocardiography showed similar cardiac function between PKM2−/− and control mice after MI. However, PKM2−/− infarcted hearts had increased abundances of transcripts associated with oxidative stress and immune responses. Immunohistochemistry revealed greater abundance of macrophages in PKM2−/− hearts prior to MI, with a small increase in CD86⁺ macrophages in PKM2−/− infarcted hearts. Elevated baseline plasma IL‐6, IL‐1β, and C‐reactive protein, and cardiac IL‐6, 3 days post‐MI, were observed in PKM2−/− mice. Oxidative lipid products were also elevated in baseline PKM2−/− hearts, while antioxidant glutathione peroxidase 4 was reduced. Greater fibrosis was seen in PKM2−/− hearts 28 days after MI. These findings suggest Pkm2 ablation primes the heart for increased oxidative stress, inflammation, and fibrosis post‐MI. The natural upregulation of PKM2 may mitigate fibrosis by reducing oxidative stress and inflammation, highlighting its protective role in the infarcted heart.

Cancer is a complex disease with profound societal and economic impacts, especially in metastatic cases where treatment challenges arise due to the absence of reliable biomarkers and effective therapies. While P21‐activated kinases (PAKs) play a key role in cancer progression, their potential as predictive markers for metastasis and therapeutic targets has not been fully explored. We hypothesized that genetic alterations in PAK isoforms could be linked to reduced overall patient survival. To investigate this, we used data from the cBioPortal for Cancer Genomics, analyzing several randomized, multicentered phase‐3 clinical trial datasets. The analysis revealed significant genetic alterations in PAK genes, particularly in cancers such as breast, prostate, pancreatic, and lung. Notably, elevated PAK expression was associated with poorer survival outcomes in prostate and breast cancer patients. In pancreatic and lung cancers, although a trend of poorer survival with PAK alterations was observed, it was not statistically significant. Our findings underscore the importance of PAK isoforms as potential biomarkers and therapeutic targets, particularly in metastatic cancers. Further research could lead to improved patient outcomes through targeted interventions aimed at PAK‐related pathways, with PAK serving as a reliable biomarker for the precise diagnosis, monitoring, and personalization of treatment strategies.

Sepsis leads to an acute breakdown of muscle to support increased caloric and amino acid requirements. Little is known about the role of adipose and muscle tissue breakdown and intestinal metabolism in glucose substrate supply during the acute phase of sepsis. In a translational porcine model of sepsis, we explored the across organ net fluxes of gluconeogenic substrates. In 13 pigs, acute sepsis was induced by IV infusion of Pseudomonas aeruginosa, while in 9 pigs saline (control) was given for 18 h. Blood samples were collected between 12 and 18 h and analyzed with HPLC and LCMS. In sepsis, glucose plasma concentration was reduced (p = 0.0028). A concordant increase in splanchnic area net release of glucose (p = 0.0049), due to reduced uptake in the portal drained viscera (PDV) (p = 0.0032) with an unchanged liver production (p = 0.7861). The hindquarter showed a higher release of alanine (p = 0.0002), glutamine (p = 0.003), and lactate (p = 0.0007), but not for glycerol (p = 0.5718). Diminished PDV uptake of gluconeogenic amino acids, increased liver uptake of these substrates (p < 0.05), while no change in liver glycerol uptake (p = 0.3170), did not lead to an increased net liver glucose release. In the acute phase of sepsis, we hypothesize an important role of altered intestinal amino acid metabolism and breakdown of muscle proteins, but not of glycolysis to support gluconeogenesis.