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A PGC-1? isoform induced by resistance training regulates skeletal muscle hypertrophy.

ABSTRACT: PGC-1? 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-1? (PGC-1?4) that results from alternative promoter usage and splicing of the primary transcript. PGC-1?4 is highly expressed in exercised muscle but does not regulate most known PGC-1? targets such as the mitochondrial OXPHOS genes. Rather, it specifically induces IGF1 and represses myostatin, and expression of PGC-1?4 in vitro and in vivo induces robust skeletal muscle hypertrophy. Importantly, mice with skeletal muscle-specific transgenic expression of PGC-1?4 show increased muscle mass and strength and dramatic resistance to the muscle wasting of cancer cachexia. Expression of PGC-1?4 is preferentially induced in mouse and human muscle during resistance exercise. These studies identify a PGC-1? protein that regulates and coordinates factors involved in skeletal muscle hypertrophy.

SUBMITTER: Ruas JL

PROVIDER: S-EPMC3520615 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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A PGC-1α isoform induced by resistance training regulates skeletal muscle hypertrophy.

Ruas Jorge L JL White James P JP Rao Rajesh R RR Kleiner Sandra S Brannan Kevin T KT Harrison Brooke C BC Greene Nicholas P NP Greene Nicholas P NP Wu Jun J Estall Jennifer L JL Irving Brian A BA Lanza Ian R IR Rasbach Kyle A KA Okutsu Mitsuharu M Nair K Sreekumaran KS Yan Zhen Z Leinwand Leslie A LA Spiegelman Bruce M BM

Cell 20121201 6

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 an ...[more]

PMID: 23217713

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Project description:ObjectiveIn this review, we critically evaluate studies directly comparing the effects of plyometric vs. resistance training on skeletal muscle hypertrophy.MethodsWe conducted electronic searches of PubMed/MEDLINE, Scopus, SPORTDiscus, and Web of Science to find studies that explored the effects of plyometric vs. resistance training on muscle hypertrophy.ResultsEight relevant studies were included in the review. Six studies compared the effects of plyometric vs. resistance training on muscle hypertrophy, while 2 studies explored the effects of combining plyometric and resistance training vs. isolated resistance training on acute anabolic signaling or muscle hypertrophy. Based on the results of these studies, we conclude that plyometric and resistance training may produce similar effects on whole muscle hypertrophy for the muscle groups of the lower extremities. Therefore, it seems that plyometric training has a greater potential for inducing increases in muscle size than previously thought. Despite the findings observed at the whole muscle level, the evidence for the effects of plyometric training on hypertrophy on the muscle fiber level is currently limited for drawing inferences. Compared to isolated resistance training, combining plyometric and resistance exercise does not seem to produce additive effects on anabolic signaling or muscle growth; however, this area requires future study. The limitations of the current body of evidence are that the findings are specific to (a) musculature of the lower extremities, (b) short-term training interventions that lasted up to 12 weeks, and (c) previously untrained or recreationally active participants.ConclusionThis review highlights that plyometric and resistance training interventions may produce similar effects on whole muscle hypertrophy, at least for the muscle groups of the lower extremities, in untrained and recreationally trained individuals, and over short-term (i.e., ≤12 weeks) intervention periods.

Project description:The factors that underpin heterogeneity in muscle hypertrophy following resistance exercise training (RET) remain largely unknown. We examined circulating hormones, intramuscular hormones, and intramuscular hormone-related variables in resistance-trained men before and after 12 weeks of RET. Backward elimination and principal component regression evaluated the statistical significance of proposed circulating anabolic hormones (e.g., testosterone, free testosterone, dehydroepiandrosterone, dihydrotestosterone, insulin-like growth factor-1, free insulin-like growth factor-1, luteinizing hormone, and growth hormone) and RET-induced changes in muscle mass (n = 49). Immunoblots and immunoassays were used to evaluate intramuscular free testosterone levels, dihydrotestosterone levels, 5?-reductase expression, and androgen receptor content in the highest- (HIR; n = 10) and lowest- (LOR; n = 10) responders to the 12 weeks of RET. No hormone measured before exercise, after exercise, pre-intervention, or post-intervention was consistently significant or consistently selected in the final model for the change in: type 1 cross sectional area (CSA), type 2 CSA, or fat- and bone-free mass (LBM). Principal component analysis did not result in large dimension reduction and principal component regression was no more effective than unadjusted regression analyses. No hormone measured in the blood or muscle was different between HIR and LOR. The steroidogenic enzyme 5?-reductase increased following RET in the HIR (P < 0.01) but not the LOR (P = 0.32). Androgen receptor content was unchanged with RET but was higher at all times in HIR. Unlike intramuscular free testosterone, dihydrotestosterone, or 5?-reductase, there was a linear relationship between androgen receptor content and change in LBM (P < 0.01), type 1 CSA (P < 0.05), and type 2 CSA (P < 0.01) both pre- and post-intervention. These results indicate that intramuscular androgen receptor content, but neither circulating nor intramuscular hormones (or the enzymes regulating their intramuscular production), influence skeletal muscle hypertrophy following RET in previously trained young men.

Project description:Aim/hypothesisThe peroxisome proliferator-activated receptor-γ coactivator α (PGC-1α) plays a critical role in the maintenance of glucose, lipid and energy homeostasis by orchestrating metabolic programs in multiple tissues in response to environmental cues. In skeletal muscles, PGC-1α dysregulation has been associated with insulin resistance and type 2 diabetes but the underlying mechanisms have remained elusive. This research aims to understand the role of TET3, a member of the ten-eleven translocation (TET) family dioxygenases, in PGC-1α dysregulation in skeletal muscles in obesity and diabetes.MethodsTET expression levels in skeletal muscles were analysed in humans with or without type 2 diabetes, as well as in mouse models of high-fat diet (HFD)-induced or genetically induced (ob/ob) obesity/diabetes. Muscle-specific Tet3 knockout (mKD) mice were generated to study TET3's role in muscle insulin sensitivity. Genome-wide expression profiling (RNA-seq) of muscle tissues from wild-type (WT) and mKD mice was performed to mine deeper insights into TET3-mediated regulation of muscle insulin sensitivity. The correlation between PGC-1α and TET3 expression levels was investigated using muscle tissues and in vitro-derived myotubes. PGC-1α phosphorylation and degradation were analysed using in vitro assays.ResultsTET3 expression was elevated in skeletal muscles of humans with type 2 diabetes and in HFD-fed and ob/ob mice compared with healthy controls. mKD mice exhibited enhanced glucose tolerance, insulin sensitivity and resilience to HFD-induced insulin resistance. Pathway analysis of RNA-seq identified 'Mitochondrial Function' and 'PPARα Pathway' to be among the top biological processes regulated by TET3. We observed higher PGC-1α levels (~25%) in muscles of mKD mice vs WT mice, and lower PGC-1α protein levels (~25-60%) in HFD-fed or ob/ob mice compared with their control counterparts. In human and murine myotubes, increased PGC-1α levels following TET3 knockdown contributed to improved mitochondrial respiration and insulin sensitivity. TET3 formed a complex with PGC-1α and interfered with its phosphorylation, leading to its destabilisation.Conclusions/interpretationOur results demonstrate an essential role for TET3 in the regulation of skeletal muscle insulin sensitivity and suggest that TET3 may be used as a potential therapeutic target for the metabolic syndrome.Data availabilitySequences are available from the Gene Expression Omnibus ( https://www.ncbi.nlm.nih.gov/geo/ ) with accession number of GSE224042.

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A PGC-1? isoform induced by resistance training regulates skeletal muscle hypertrophy.

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A PGC-1α isoform induced by resistance training regulates skeletal muscle hypertrophy.

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