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Acute Response of PGC-1 and IGF-1 Isoforms to Maximal Eccentric Exercise in Skeletal Muscle of Postmenopausal Women
Abstract and Figures
PGC-1α4, a novel isoform of the transcriptional coactivator PGC-1α, was recently postulated to modulate the expression of anabolic and catabolic genes and therefore regulate skeletal muscle hypertrophy. Resting levels of PGC-1α4 mRNA expression were found to increase in healthy adults after resistance training. However, the acute effect of resistance exercise (RE) on PGC-1α4 expression in populations prone to progressive muscle loss, such as postmenopausal women, has not been evaluated. Here we investigated alterations in mRNA expression of PGC-1α4 and PGC-1α1, a regulator of muscle oxidative changes, in postmenopausal women following high-intensity eccentric RE, and analyzed these findings with respect to changes in IGF-1 and catabolic gene expression. Nine postmenopausal women (57.9 ± 3.2 yr) performed 10 sets of 10 maximal eccentric repetitions of single-leg extension with 20 second rest periods between sets. Muscle biopsies were obtained from the vastus lateralis of the exercised leg before and 4 hours after the RE bout with mRNA expression determined by qRT-PCR. No significant changes in the mRNA expression of either PGC-1α isoform were observed following acute eccentric RE (P > 0.05). IGF-1Ea mRNA expression significantly increased (P < 0.05) while IGF-1Eb and MGF did not significantly change (P > 0.05). PGC-1α4 mRNA expression was associated with reduced mRNA expression of the catabolic gene myostatin (R = -.88, P < 0.01), while MGF mRNA expression was associated with reduced mRNA expression of the catabolic gene FOXO3A (R = -.81, P < 0.05). These data demonstrate an attenuated response of PGC-1α isoforms to an acute bout of maximal eccentric exercise with short rest periods in postmenopausal women.
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... In both Vitro and Vivo conditions, PGC-1α4 stimulates muscle hypertrophy, and animals with overexpression of PGC-1α4 showed resistance to the effects of post-cancer muscle loss [6]. However, Lundberg et al. found that PGC -1α4 is not associated with muscle hypertrophy after resistance training for 5 weeks [8], and no change reported in PGC1α-4 expression following a resistance training bout [9]. Although, a correlation between PGC-1α1 and hypertrophy or muscle strength are yet reported [10]. ...
... Previously, the significant association among IGF-1, PGC-1α4 with myostatin has been detected [6,9,12]. In this regard, total PGC-1α mRNA increased following a resistance exercise bout, where myostatin mRNA expression has been decreased [12]. ...
... It has been found that a combination of resistance exercise with high intensity interval training (HIIT) developed greater PGC-1α4 compared to only resistance exercise [31]. However, Dieli-Conwright et al. have found no substantial differences in PGC-1α mRNA after eccentric contraction [9]. Moreover, aerobic resistance exercise increased PGC-1α mRNA in train and untrained subjects [33], whereas PGC-1a4 was not preferentially induced by resistance exercise in trained and untrained muscles [8]. ...
Muscle contraction stimulates a transient change of myogenic factors, partly related to the mode of contractions. Here, we assessed the response of IGF-1Ea, IGF-1Eb, IGF-1Ec, PGC1α-1, PGC1α-4, and myostatin to the eccentric Vs. the concentric contraction in human skeletal muscle. Ten healthy males were performed an acute eccentric and concentric exercise bout (n = 5 per group). For each contraction type, participants performed 12 sets of 10 repetitions knee extension by the dominant leg. Baseline and post-exercise muscle biopsy were taken 4 weeks before and immediately after experimental sessions from Vastus Lateralis muscle. Genes expression was measured by real-time PCR technique. There was a significant increase in PGC1α-1, PGC1α-4, IGF-1Ea and, IGF-1Eb mRNA after concentric contraction (p ≤ 0.05), while the PGC1α-4 and IGF-1Ec significantly increased after eccentric contraction (p ≤ 0.05). It is intriguing to highlight that; no significant differences between groups were evident for changes in any variables following exercise bouts (p ≥ 0.05). Our results found that concentric and eccentric contractions presented different responses in PGC1α-1, IGF-1Ea, IGF-1Eb, and IGF-1Ec mRNA. However, a similar significant increase in mRNA content was observed in PGC1α-4. Further, no apparent differences could be found between the response of genes to eccentric and concentric contraction.
... In rats, either a single bout or a six-week eccentric resistance exercise has elevated PGC-1α mRNA expression as well as serum levels of irisin, which has further been enhanced with β-hydroxy-β-methyl butyrate supplementation [97,98]. Controversially, one acute bout of maximal single-leg eccentric knee extension exercise has failed to increase postexercise levels of PGC-1α mRNA in postmenopausal women [99]. ...
There is a growing body of evidence showing the importance of physical activity against civilization-induced metabolic diseases, including type 2 diabetes (T2DM) and obesity. Eccentric contraction, when skeletal muscles generate force by lengthening, is a unique type of skeletal muscle activity. Eccentric contraction may lead to better power production characteristics of the muscle because eccentric contraction requires less energy and can result in higher tension. Therefore, it is an ideal tool in the rehabilitation program of patients. However, the complex metabolic effect (i.e., fat mass reduction, increased lipid oxidation, improvement in blood lipid profile, and increased insulin sensitivity) of the eccentric contraction alone has scarcely been investigated. This paper aims to review the current literature to provide information on whether eccentric contraction can influence metabolic health and body composition in T2DM or obesity. We also discussed the potential role of myokines in mediating the effects of eccentric exercise. A better understanding of the mechanism of eccentric training and particularly their participation in the regulation of metabolic diseases may widen their possible therapeutic use and, thereby, may support the fight against the leading global risks for mortality in the world.
... Based on the analysis results of moderate-intensity exercise, both interval and continuous exercise increase the circadian cycle changes of the thermogenic genes PGC-1α and FNDC-5 at 10 minutes, 6 hours, and 24 hours after exercise, compared to the control group. The increase in PGC-1α after exercise stimulates a growth in FNDC-5 protein, which cleavages to form irisin [54], activating the UCP-1 thermogenic gene to enhance thermogenesis [14]. Previous studies also reported higher PGC-1α in experimental mice after swimming treatment than in the control group [55]. ...
Thermogenesis is associated with oxidation activity in muscle and fat tissue, the target of non-pharmacological therapy in preventing the increase in obesity. This research was designed to reveal the circadian profile of thermogenic gene expression after the acute interval and continuous moderate-intensity exercise. The subjects were 22 randomly selected obese adolescent females who met the predetermined inclusion criteria. The study subjects were then divided into three groups: control group (CG), acute interval moderate-intensity exercise group (AIMIE), and acute continuous moderate-intensity exercise group (ACMIE). Acute interval and continuous exercise were performed by running on a treadmill for 40-45 minutes, while moderate-intensity was defined as 60%-70% of the maximum heart rate (HRmax). The blood samples were collected initially (pre-exercise), followed by 10 minutes, 6 hours, and 24 hours post-acute interval and continuous moderate-intensity exercise treatment. Measurement of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) and fibronectin type III domain 5 (FNDC-5) expressions in protein level were confirmed by enzyme-linked immunosorbent assay (ELISA) method. Data were analyzed using one way-ANOVA and two way-ANOVA with a significant level of 5%. The findings suggest a substantial increase in the expression of PGC-1α and FNDC-5 after exercise compared to before the workout. A significant difference in PGC-1α and FNDC-5 expressions between the control group compared to AIMIE and ACMIE (p ≤ 0.05) has been observed. However, there is no significant difference in PGC-1α and FNDC-5 expressions after exercise between AIMIE and ACMIE (p ≥ 0.05). In conclusion, acute interval and continuous moderate-intensity exercise increase the expression of thermogenesis-related genes. Hence, acute interval and continuous moderate-intensity exercise might be potential non-pharmacological therapy to prevent, reduce, and control the increasing prevalence of obesity.
... Insulin-like growth factor 1 (IGF-1) is synthesized mainly in the liver and acts as a growth and differentiation factor. IGF-1 is also synthesized by skeletal muscle after physical activity [151][152][153][154]. Apart from its prominent role in muscle hypertrophy and regeneration, IGF-1 exerts protection against oxidative stress-induced cellular injury. ...
There is a growing body of evidence showing the importance of physical activity against acute ischemic events in various organs. Ischemia/reperfusion injury (I/R) is characterized by tissue damage as a result of restriction and subsequent restoration of blood supply to an organ. Oxidative stress due to increased reactive oxygen species formation and/or insufficient antioxidant defense is considered to play an important role in I/R. Physical activity not only decreases the general risk factors for ischemia but also confers direct anti-ischemic protection via myokine production. Myokines are skeletal muscle-derived cytokines, representing multifunctional communication channels between the contracting skeletal muscle and other organs through an endocrine manner. In this review, we discuss the most prominent members of the myokines (i.e., brain-derived neurotrophic factor (BDNF), cathepsin B, decorin, fibroblast growth factors-2 and-21, follistatin, follistatin-like, insulin-like growth factor-1; interleukin-6, interleukin-7, interleukin-15, irisin, leukemia inhibitory factor, meteorin-like, myonectin, musclin, myostatin, and osteoglycin) with a particular interest in their potential influence on reactive oxygen and nitrogen species formation or antioxidant capacity. A better understanding of the mechanism of action of myokines and particularly their participation in the regulation of oxidative stress may widen their possible therapeutic use and, thereby, may support the fight against I/R.
... However, in 2016, Kiwata et al. reported that PGC-1α resting-state increases in healthy people after resistance training. Conversely, it did not have any effect on the expression of PGC-1α in menopausal females (30). In 2018, Menishko et al. studied the simultaneous effect of training and calorie restriction on insulin resistance and PGC-1α expression in old obese people. ...
Background: Reduced physical activity can cause obesity and metabolic syndrome, leading to fibrosis in cardiac muscles and premature cardiac aging. Physical activity, along with herbal supplements, can have a synergistic effect on preventing cardiac muscle proteolysis. Objectives: In this study, the effects of curcumin and resistance training were assessed on cardiac muscle atrophy in obese rats. Methods: Twenty-four male Sprague rats were categorized into four groups, including the placebo, resistance training, curcumin, and resistance training + curcumin. Resistance training was performed three times a week with three sets in each session, repeated five times for eight weeks. During this time, 150 mg/kg curcumin was administered through gavage. Twenty-four hours after finishing resistance training, surgery was performed on the cardiac muscle, and gene expressions of PGC1-α, FOXO1, Murf-1, Atrogin, Collagen1, and Collagen 3 were assessed with real-time PCR. Results: The expression of PGC1-α and FOXO1 genes in both resistance training and resistance training+curcumin groups significantly increased and decreased, respectively, compared to the control group (P = 0.001). The MuRF1 expression in the curcumin+resistance training group decreased significantly (P = 0.013) compared to the placebo and curcumin groups. The expression of collagen type 1 and type 2 in all the three treatment groups had significant decreases compared to the placebo group (P < 0.05). Conclusions: Considering the results of this study, resistance training and curcumin supplement each alone can prevent cardiac muscle atrophy. However, the simultaneous use of curcumin supplement and resistance training can lead to synergistic effects.
... Additionally, rats with spinal cord injury exhibited IGF-1 upregulation in the soleus after treadmill training, which resulted in the upregulation of muscle regeneration markers, such as myogenin and MyoD [110]. Significantly increased IGF-1 mRNA expression has been reported in postmenopausal women after a single-leg extension exercise [111]. ...
Physical activity has been found to aid the maintenance of health in the elderly. Exercise-induced skeletal muscle contractions lead to the production and secretion of many small proteins and proteoglycan peptides called myokines. Thus, studies on myokines are necessary for ensuring the maintenance of skeletal muscle health in the elderly. This review summarizes 13 myokines regulated by physical activity that are affected by aging and aims to understand their potential roles in metabolic diseases. We categorized myokines into two groups based on regulation by aerobic and anaerobic exercise. With aging, the secretion of apelin, β-aminoisobutyric acid (BAIBA), bone morphogenetic protein 7 (BMP-7), decorin, insulin-like growth factor 1 (IGF-1), interleukin-15 (IL-15), irisin, stromal cell-derived factor 1 (SDF-1), sestrin, secreted protein acidic rich in cysteine (SPARC), and vascular endothelial growth factor A (VEGF-A) decreased, while that of IL-6 and myostatin increased. Aerobic exercise upregulates apelin, BAIBA, IL-15, IL-6, irisin, SDF-1, sestrin, SPARC, and VEGF-A expression, while anaerobic exercise upregulates BMP-7, decorin, IGF-1, IL-15, IL-6, irisin, and VEGF-A expression. Myostatin is downregulated by both aerobic and anaerobic exercise. This review provides a rationale for developing exercise programs or interventions that maintain a balance between aerobic and anaerobic exercise in the elderly.
... The effects of eccentric exercise on serum IGF-1 has also been a topic of investigation. It has been reported that acute eccentric resistance exercise induces an increase in muscle IGF-1 gene expression in humans (Dieli-Conwright et al., 2016), and that this increase in serum IGF-1 in turn, enhances the response to eccentric arm exercise (Zebrowska et al., 2013). Townsend et al. showed that this increased response due to IGF-1 occurs after just one session of heavy resistance exercise (Townsend et al., 2015). ...
... One study indicated that exercise training is a more effective at reducing age-associated inflammation than resveratrol supplementation and that PGC-1α was required for these antiinflammatory effects (69). Exercise training of skeletal muscle changes kynurenine metabolism and protects from stress-induced depression (70)(71)(72)(73). Activation of PGC-1α1 can increase skeletal muscle expression of kynurenine aminotransferases, which facilitate the conversion of kynurenine into kynurenic acid, a metabolite unable to cross the bloodbrain barrier (73). ...
Dementia has become a major health concern for the aging population of the United States. Studies indicate that participation in moderate exercise, with training, has been shown to have a beneficial impact on cognition. Thus, exercise and its effects on cognitive function has become an important area of research. This review summarizes the current literature on the potential mechanisms of the benefits of exercise for cognitive function.
Concurrent training involving resistance and endurance exercise may augment the benefits of single-mode training for the purpose of improving health. However, muscle adaptations, associated with resistance exercise, may be blunted by a subsequent bout of endurance exercise, via molecular interference. High-intensity interval training (HIIT), generating similar adaptations to endurance exercise, may offer an alternative exercise mode to traditional endurance exercise. This study examined the influence of an acute HIIT session on the molecular responses following resistance exercise in untrained skeletal muscle. Ten male participants performed resistance exercise (4 × 8 leg extensions, 70% 1RM, (RE)) or RE followed by HIIT (10 × 1 min at 90% HRmax, (RE+HIIT)). Muscle biopsies were collected from the vastus lateralis before, 2 and 6 h post-RE to determine intramuscular protein phosphorylation and mRNA responses. Phosphorylation of Akt (Ser(473)) decreased at 6 h in both trials (P < 0.05). Phosphorylation of mTOR (Ser(2448)) was higher in RE+HIIT (P < 0.05). All PGC-1α mRNA variants increased at 2 h in RE+HIIT with PGC-1α and PGC-1α-ex1b remaining elevated at 6 h, whereas RE-induced increases at 2 and 6 h for PGC-1α-ex1b only (P < 0.05). Myostatin expression decreased at 2 and 6 h in both trials (P < 0.05). MuRF-1 was elevated in RE+HIIT versus RE at 2 and 6 h (P < 0.05). Atrogin-1 was lower at 2 h, with FOXO3A downregulated at 6 h (P < 0.05). These data do not support the existence of an acute interference effect on protein signaling and mRNA expression, and suggest that HIIT may be an alternative to endurance exercise when performed after resistance exercise in the same training session to optimize adaptations.
© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.
Mitochondrial dysfunction may contribute to age-associated muscle atrophy. Previous data has shown that resistance exercise (RE) increases mitochondrial gene expression and enzyme activity in older adults; however, the acute response to RE has not been well characterized. To characterize the acute mitochondrial response to unaccustomed RE, healthy young (21±3 y) and older (70±4 y) men performed a unilateral RE bout for the knee extensors. Muscle biopsies were taken at rest and 3, 24 and 48 h following leg press and knee extension exercise. The expression of the mitochondrial transcriptional regulator PGC-1α mRNA was increased at 3 h post-exercise; however, all other mitochondrial variables decreased over the post-exercise period, irrespective of age. ND1, ND4 and CS mRNA were all lower at 48 h post-exercise, along with specific protein subunits of complex II, III, IV and ATP synthase. Mitochondrial DNA (mtDNA) copy number decreased by 48 h post-exercise, and mtDNA deletions were higher in the older adults and remained unaffected by acute exercise. Elevated mitophagy could not explain the reduction in mitochondrial proteins and DNA, as there was no increase in ubiquitinated VDAC or its association with Pink1 or Parkin, and elevated p62 content indicated an impairment or reduction in autophagocytic flux. In conclusion, age did not influence the response of specific mitochondrial transcripts, proteins and DNA to a bout of RE.
Copyright © 2014, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology.
This study assessed markers of muscle damage and training adaptations to eccentric-overload flywheel resistance exercise (RE) in men and women.
Dynamic strength (1 RM), jump performance, maximal power at different percentages of 1 RM, and muscle mass in three different portions of the thigh were assessed in 16 men and 16 women before and after 6 weeks (15 sessions) of flywheel supine squat RE training. Plasma creatine kinase (CK) and lactate dehydrogenase (LDH) concentrations were measured before, 24, 48 and 72 h after the first and the last training session.
After training, increases in 1 RM were somewhat greater (interaction P < 0.001) in men (25 %) than in women (20 %). Squat and drop jump height and power performance at 50, 60, 70 and 80 % of 1 RM increased after training in both sexes (P < 0.05). Power improvement at 80 % of 1 RM was greater (interaction P < 0.02) in men than women. Muscle mass increased ~5 % in both groups (P < 0.05). CK increased in men after the first training session (P < 0.001), whereas the response in women was unaltered. In both sexes, LDH concentration was greater after the first training session compared with basal values (P < 0.05). After the last session, CK and LDH remained at baseline in both groups.
These results suggest that although improvements in maximal strength and power at high loads may be slightly greater for men, eccentric-overload RE training induces comparable and favorable gains in strength, power, and muscle mass in both men and women. Equally important, it appears muscle damage does not interfere with the adaptations triggered by this training paradigm.
Recently, a truncated peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) splice variant, PGC-1α4, that originates from the alternative promoter was shown to be induced by resistance exercise and to elicit muscle hypertrophy without coactivation of "classical" PGC-1α targets involved in mitochondrial biogenesis and angiogenesis. In order to test if distinct physiological adaptations are characterized by divergent induction of PGC-1α splice variants, we investigated the expression of truncated and nontruncated PGC-1α splice variants and PGC-1α transcripts originating from the alternative and the proximal promoter, in human skeletal muscle in response to endurance and resistance exercise. Both total PGC-1α and truncated PGC-1α mRNA expression were increased 2 h after endurance (P < 0.01) and resistance exercise (P < 0.01), with greater increases after endurance exercise (P < 0.05). Expression of nontruncated PGC-1α increased significantly in both exercise groups (P < 0.01 for both groups) without any significant differences between the groups. Both endurance and resistance exercise induced truncated as well as nontruncated PGC-1α transcripts from both the alternative and the proximal promoter. Further challenging the hypothesis that induction of distinct PGC-1α splice variants controls exercise adaptation, both nontruncated and truncated PGC-1α transcripts were induced in AICAR-treated human myotubes (P < 0.05). Thus, contrary to our hypothesis, resistance exercise did not specifically induce the truncated forms of PGC-1α. Induction of truncated PGC-1α splice variants does not appear to underlie distinct adaptations to resistance versus endurance exercise. Further studies on the existence of numerous splice variants originating from different promoters are needed.
The transcriptional coactivator peroxisome proliferator-activator receptor gamma coactivator (PGC)-1α is required for full hypoxic induction of vascular endothelial growth factor (VEGF) in skeletal muscle cells. Under normoxic conditions, PGC-1α also strongly induces mitochondrial biogenesis, but PGC-1α does not activate this program under hypoxic conditions. How this specificity is achieved is not known. We show here that hypoxia specifically induces NT-PGC-1α, a known alternatively spliced species encoding for a truncated form of PGC-1α. NT-PGC-1α strongly induces VEGF expression, while having little effect on mitochondrial genes. Conditioned medium from cells expressing NT-PGC-1α robustly induces endothelial migration and tube formation, hallmarks of angiogenesis. Transgenic expression of NT-PGC-1α in skeletal muscle in mice induces angiogenesis in vivo. Finally, knockdown of NT-PGC-1α and HIF-1α abrogates the induction of VEGF in response to hypoxia. NT-PGC-1α thus confers angiogenic specificity to the PGC-1α-mediated hypoxic response in skeletal muscle cells.
PGC-1α is a transcriptional coactivator induced by exercise that gives muscle many of the best known adaptations to endurance-type exercise but has no effects on muscle strength or hypertrophy. We have identified a form of PGC-1α (PGC-1α4) that results from alternative promoter usage and splicing of the primary transcript. PGC-1α4 is highly expressed in exercised muscle but does not regulate most known PGC-1α targets such as the mitochondrial OXPHOS genes. Rather, it specifically induces IGF1 and represses myostatin, and expression of PGC-1α4 in vitro and in vivo induces robust skeletal muscle hypertrophy. Importantly, mice with skeletal muscle-specific transgenic expression of PGC-1α4 show increased muscle mass and strength and dramatic resistance to the muscle wasting of cancer cachexia. Expression of PGC-1α4 is preferentially induced in mouse and human muscle during resistance exercise. These studies identify a PGC-1α protein that regulates and coordinates factors involved in skeletal muscle hypertrophy.
The aim of the present study was to examine the effects of ageing and training status on (1) markers of skeletal muscle mitochondrial content and (2) the ability to activate the acute signalling pathways associated with regulating exercise-induced mitochondrial biogenesis. Muscle biopsies were obtained from the vastus lateralis muscle of young untrained (24 ± 4 years, n = 6; YU), young trained (22 ± 3 years, n = 6; YT), old untrained (65 ± 6 years, n = 6; OU) and old trained (64 ± 3 years, n = 6; OT) healthy males before and after (3 h and 3 days post-exercise) completion of high-intensity interval cycling exercise. In resting muscle, lifelong training preserved mtDNA, PGC-1α and COXIV protein content such that muscles from OT individuals were comparable to muscles from both YU and YT individuals, whereas lifelong sedentary behaviour reduced such markers of mitochondrial content. Regardless of age or training status, acute exercise induced comparable increases in p38MAPK phosphorylation immediately post-exercise, PGC-1α and COXIV mRNA expression at 3 h post-exercise and COXIV protein at 3 days post-exercise. Data demonstrate that lifelong endurance training preserves skeletal muscle PGC-1α content and that despite the mitochondrial dysfunction typically observed with sedentary ageing, muscles from sedentary elderly individuals retain the capacity to activate the acute signalling pathways associated with regulating the early processes of mitochondrial biogenesis. We consider our data to have immediate translational potential as they highlight the potential therapeutic effects of exercise to induce skeletal muscle mitochondrial biogenesis persist late in adulthood, even after a lifetime of physical inactivity.
Designing PCR and sequencing primers are essential activities for molecular biologists around the world. This chapter assumes acquaintance with the principles and practice of PCR, as outlined in, for example, refs. 1, 2, 3, 4.
Aged skeletal muscle demonstrates declines in muscle mass and deterioration of mitochondrial content and function. Peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) plays an important role in promoting muscle mitochondrial biogenesis in response to exercise training, but its role in senescent muscle is not clear. In the present study we hypothesize that a downregulation of the PGC-1α signaling pathway contributes to mitochondrial deterioration in aged muscle whereas endurance training ameliorates the deficits. Three groups of Fischer 344/BNF1 rats were used: young, sedentary (Y, 4 mo); old, sedentary (O, 22 mo); and old trained (OT, 22 mo), subjected to treadmill running at 17.5 m/min, 10% grade for 45 min/day, 5 days/week for 12-weeks. PGC-1α mRNA and nuclear PGC-1α protein content in the soleus muscle were both decreased in O vs. Y rats, whereas OT rats showed a 2.3 and 1.8-fold higher PGC-1α content than O and Y rats, respectively (P<0.01). Mitochondrial transcription factor A (Tfam), cytochrome c (Cyt c) and mitochondrial (mt) DNA contents were significantly decreased in O vs. Y rats, but elevated by 2.2 (P<0.01), 1.4 (P<0.05) and 2.4-fold (P<0.01), respectively, in OT vs. O rats. In addition, Tfam and mtDNA showed 1.6 and 1.8-fold (P<0.01) higher levels, respectively, in OT vs. Y rats. These adaptations were accompanied by significant increases in the expression of the phosphorylated form of AMP-activated kinase (AMPK)(P<0.01), p38 mitogen-activated kinase (MAPK)(P<0.05) and silent mating type information regulator 2 homolog 1 (SIRT1) (P<0.01) in OT rats. Furthermore, OT rats showed great levels of phosphorylation in cAMP responsive element binding protein (p-CREB) and DNA binding compared to O and Y rats. These data indicate that endurance training can attenuate aging-associated decline in mitochondrial protein synthesis in skeletal muscle partly due to upregulation of PGC-1α signaling.
Muscle wasting is associated with a wide range of catabolic diseases. This debilitating loss of muscle mass and functional capacity reduces the quality of life and increases the risks of morbidity and mortality. Major progress has been made in understanding the biochemical mechanisms and signaling pathways regulating muscle protein balance under normal conditions and the enhanced protein loss in atrophying muscles. It is now clear that activation of myostatin/activin signaling is critical in triggering the accelerated muscle catabolism that causes muscle loss in multiple disease states. Binding of myostatin and activin to the ActRIIB receptor complex on muscle cell membrane leads to activation of Smad2/3-mediated transcription, which in turn stimulates FoxO-dependent transcription and enhanced muscle protein breakdown via ubiquitin-proteasome system and autophagy. In addition, Smad activation inhibits muscle protein synthesis by suppressing Akt signaling. Pharmacological blockade of the myostatin/activin-ActRIIB pathway has been shown to prevent or reverse the loss of muscle mass and strength in various disease models including cancer cachexia and renal failure. Moreover, it can markedly prolong the lifespan of animals with cancer-associated muscle loss. Furthermore, inhibiting myostatin/activin actions also improves insulin sensitivity, reduces excessive adiposity, attenuates systemic inflammation, and accelerates bone fracture healing in disease models. Based on these exciting advances, the potential therapeutic benefits of myostatin/activin antagonism are now being tested in multiple clinical settings.