The transcriptional coactivator PGC-1α is dispensable for chronic overload-induced skeletal muscle hypertrophy and metabolic remodeling

Abstract

Skeletal muscle mass loss and dysfunction have been linked to many diseases. Conversely, resistance exercise, mainly by activating mammalian target of rapamycin complex 1 (mTORC1), promotes skeletal muscle hypertrophy and exerts several therapeutic effects. Moreover, mTORC1, along with peroxisome proliferatoractivated receptor γ coactivator 1α (PGC-1α), regulates skeletal muscle metabolism. However, it is unclear whether PGC-1α is required for skeletal muscle adaptations after overload. Here we show that although chronic overload of skeletal muscle via synergist ablation (SA) strongly induces hypertrophy and a switch toward a slow-contractile phenotype, these effects were independent of PGC-1α. In fact, SA down-regulated PGC-1α expression and led to a repression of energy metabolism. Interestingly, however, PGC-1α deletion preserved peak force after SA. Taken together, our data suggest that PGC-1α is not involved in skeletal muscle remodeling induced by SA.muscle overload | transcriptional regulation | resistance training S keletal muscle size exhibits drastic changes throughout life, mainly dependent on mechanical load and nutritional supply (1). For example, loss of muscle mass is observed during immobilization and starvation, but also under pathological conditions like heart failure and cancer (2). To date, resistance exercise is considered as one of the most efficient ways to induce skeletal muscle hypertrophy and to revert the adverse effects of muscle wasting (2, 3). However, because pharmacological interventions are scarce, identification of the molecular regulation of muscle remodeling via resistance exercise is of great therapeutic interest.Activation of mammalian target of rapamycin complex 1 (mTORC1) is the main regulatory step by which resistance exercise enhances protein synthesis and skeletal muscle size (4). In fact, inhibition of mTORC1 drastically abrogates plantaris hypertrophy via chronic overload (5), even though muscle size is not affected uniformly by muscle knockout of the mTORC1 inhibitor tuberous sclerosis complex 1 (6). Interestingly, the activity of the mTORC1 protein kinase complex positively correlates with oxidative capacity (7,8). Moreover, mTORC1 is recruited to the promoter of a wide range of metabolism-related genes to regulate their expression (9-11). In skeletal muscle, mTORC1 regulates oxidative metabolism by facilitating the activation of Yin Yang 1 by the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) (10, 12). The physiological context in which the mTORC1-PGC-1α axis regulates energy metabolism, however, is unknown.Protein degradation is an important limiting factor of skeletal muscle hypertrophy. This process is fine-tuned by the transcription factor forkhead box O3 (FOXO3), which regulates the expression of the E3 ubiquitin ligases muscle ring finger protein 1 (MuRF1) and F-box protein 32 (Fbxo32/atrogin-1) (13). Interestingly, PGC-1α represses FOXO3 activity and consequently ameliorates skeletal muscle mass loss during denervation and aging (14-16)...

The hitchhiker’s guide to PGC-1α isoform structure and biological functions

“…In the same study, we demonstrated that PGC-1α4 is sufficient to induce skeletal muscle hypertrophy. A different group has reported that mice lacking expression of all (known) PGC-1α proteins in skeletal muscle still undergo hypertrophy induced by the synergistic ablation model [63]. We cannot rule out either the existence of additional isoforms that might account for those particular effects or compensatory mechanisms due to the disruption of the Pgc-1α gene since the embryonic state.…”

PGC‐1α affects aging‐related changes in muscle and motor function by modulating specific exercise‐mediated changes in old mice

“…Total protein was recovered from quadriceps muscles as described in Perez‐Schindler, Summermatter, Santos, Zorzato, and Handschin (2013). Equal amounts of protein were migrated on mini‐TGX 4‐20% stain free precast gel (Bio‐Rad, 4568096) and labeled with the in‐gel trihalo compounds under UV for 1 min.…”

Transcriptional Network Analysis in Muscle Reveals AP-1 as a Partner of PGC-1α in the Regulation of the Hypoxic Gene Program

“…The binding peak regions were aligned with orthologous regions from 6 other mammalian species-human (hg18), rhesus macaque (rheMac2), dog (canFam2), horse (equCab1), cow (bosTau3), and opossum (monDom4)-using TCoffee (18). A collection of 190 mammalian regulatory motifs (position weight matrices [WMs]) representing the binding specificities of approximate 350 mouse TFs (in many cases, sequence specificities of multiple closely related TFs were represented with the same WM) were downloaded from the SwissRegulon website (19). TFBSs for all known motifs were predicted using the MotEvo algorithm (20) on the alignments of all 7,512 peak sequences.…”

“…Subsequently, probes were classified as expressed or nonexpressed by using the "Mclust" R package (22), and after removal of nonexpressed probes, the intensity values were quantile normalized across all samples. Using mapping of the probes to the UCSC collection of mouse mRNAs, probes were then associated with a comprehensive collection of mouse promoters available from the SwissRegulon database (19). The log 2 expression level of a given promoter was calculated as the weighted average of the expression levels of all probes associated with it.…”