Editors' ChoicePhysiology

One Gene, Two Paths to Muscle Fitness

Science Signaling  01 Jan 2013:
Vol. 6, Issue 256, pp. ec1
DOI: 10.1126/scisignal.2003914

Resistance training, such as weight lifting, has many important health benefits. Maintenance of muscle mass and strength is regulated by the insulin-like growth factor 1 (IGF1) and myostatin pathways. PGC-1α (peroxisome proliferator–activated receptor-γ coactivator), a transcriptional coactivator of genes involved in energy metabolism, is induced by exercise and improves muscle endurance. Ruas et al. identified an isoform of PGC-1α, termed PGC-1α4, which is generated by a second promoter in the Pgc-1α gene. The messenger RNA (mRNA) for both PGC-1α4 and PGC-1α1 (previously PGC-1α) was detected in mouse skeletal muscle and brown fat. However, unlike PGC-1α1, for which the mRNA increases in response to either resistance or endurance exercise, the mRNA for PGC-1α4 in skeletal muscle increased only in people who performed resistance-based exercise. Transcriptional analysis determined that PGC-1α4 produced a gene expression profile in primary myotubes distinct from that regulated by PGC-1α1. In primary myotubes overexpressing PGC-1α4, the mRNA abundance of genes in the IGF1 signaling pathway, particularly IGF1, was increased, whereas the mRNA abundance of myostatin, a negative regulator of muscle protein synthesis and size, was decreased. Regulatory chromatin regions associated with IGF1 and myostatin were acetylated and methylated, respectively, indicating that PGC-1α4 may induce chromatin modifiers to regulate gene expression. Both in vitro and in vivo models supported a critical role for PGC-1α4 in mediating hypertrophy through the IGF1 pathway. The β-adrenergic agonist clenbuterol strongly induced both hypertrophy and PGC-1α4–encoding mRNA in myotubes. Inhibition of the IGF1 receptor blocked the hypertrophic response of cultured myotubes in which PGC-1α4 was overexpressed. PGC-1α4 overexpression suppressed muscle atrophy triggered with a disuse protocol that produced atrophy of the hindlimb muscle in the control animals. Furthermore, transgenic mice (Myo-PGC-1α4), expressing PGC-1α4 from the muscle-specific myogenin promoter, had increased abundance of PGC-1α4 mRNA in muscle and displayed increased muscle mass and strength and reduced fat deposits. The muscles of Myo-PGC-1α4 mice also had reduced myostatin mRNA and SMAD phosphorylation, a marker of myostatin signaling. Although Myo-PGC-1α4 mice showed no difference in tumor growth compared with wild-type mice following inoculation with Lewis lung carcinoma cells, they exhibited decreased muscle wasting, fatigue, and glucose intolerance, all traits associated with cancer cachexia. These findings introduced a new potential target to therapeutically modulate muscle mass and strength maintenance in aging, cancer, and muscular dystrophies.

J. L. Ruas, J. P. White, R. R. Rao, S. Kleiner, K. T. Brannan, B. C. Harrison, N. P. Greene, J. Wu, J. L. Estall, B. A.Irving, I. R. Lanza, K. A. Rasbach, M. Okutsu, K. Sreekumaran Nair, Z. Yan, L. A. Leinwand, B. M. Spiegelman, A PGC-1α isoform induced by resistance training regulates skeletal muscle hypertrophy. Cell 151, 1319–1331 (2012). [PubMed]