Peroxisome Proliferator-activated Receptor γ Coactivator 1α or 1β Overexpression Inhibits Muscle Protein Degradation, Induction of Ubiquitin Ligases, and Disuse Atrophy

Abstract

Overexpression of the transcriptional coactivator peroxisome proliferator-activated receptor ␥ coactivator 1␣ (PGC-1␣), like exercise, increases mitochondrial content and inhibits muscle atrophy. To understand these actions, we tested whether PGC-1␣ or its close homolog, PGC-1␤, influences muscle protein turnover. In myotubes, overexpression of either coactivator increased protein content by decreasing overall protein degradation without altering protein synthesis rates. Elevated PGC-1␣ or PGC-1␤ also prevented the acceleration of proteolysis induced by starvation or FoxO transcription factors and prevented the induction of autophagy and atrophy-specific ubiquitin ligases by a constitutively active FoxO3. In mouse muscles, overexpression of PGC-1␤ (like PGC-1␣) inhibited denervation atrophy, ubiquitin ligase induction, and transcription by NFB. However, increasing muscle PGC-1␣ levels pharmacologically by treatment of mice with 5-aminoimidazole-4-carboxamide 1-␤-D-ribofuranoside failed to block loss of muscle mass or induction of ubiquitin ligases upon denervation atrophy, although it prevented loss of mitochondria. This capacity of PGC-1␣ and PGC-1␤ to inhibit FoxO3 and NFB actions and proteolysis helps explain how exercise prevents muscle atrophy.The mass of a muscle and its functional capacity are determined by the balance between rates of protein synthesis and protein degradation. The rapid, debilitating loss of muscle that occurs upon inactivity, nerve damage, and in many systemic diseases (e.g. diabetes, cancer, sepsis, or renal failure) is characterized by an increased rate of protein degradation (1, 2) and coordinated changes in the expression of a set of atrophy-related genes, which have been termed "atrogenes" (3, 4). Many of these genes are induced by the FoxO family of transcription factors (5, 6), which is activated in atrophying muscles. In fact, activated FoxO3 alone stimulates overall protein degradation by both the ubiquitin-proteasome and the autophagic-lysosomal systems (7,8) and induces fiber atrophy (5). Two FoxOinduced genes are particularly important in enhancing proteolysis, the muscle-specific ubiquitin ligases, Atrogin1/MAFBx and MuRF1 (5, 9, 10), and muscles that lack either of these ligases show reduced fiber atrophy upon denervation (9). Another transcription factor that plays an essential role in muscle atrophy is NFB. Although activation of the NFB pathway is sufficient to induce muscle wasting (11, 12), its precise role and the factors that control its activity in muscle are still poorly understood.Despite appreciable recent progress in understanding the biochemical basis of atrophy, no pharmaceutical agents are available to inhibit this highly debilitating process. Exercise can protect against disuse atrophy as well as various systemic types of muscle wasting (13-15), but the mechanisms by which contractile activity reduces atrophy remain unclear. In principle, contractile activity may somehow enhance protein synthesis, suppress overall protein breakdown, and/or block the atrophy...

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

“…Consistently, we have previously shown that a cluster of genes related to ribosomes and anabolic pathways is down-regulated in mTg skeletal muscle (32). Finally, in vitro, PGC-1α does not regulate the rate of protein synthesis in C 2 C 12 myotubes (14). As a consequence, the assessment of a wide range of parameters related to skeletal muscle hypertrophy revealed that the overall effect of SA was not different in mTg or mKO mice.…”

“…The link between mTORC1 and skeletal muscle metabolism is thought to be PGC-1α (10,12). PGC-1α and PGC-1α4 positively modulate skeletal muscle mass under catabolic conditions (14,16,17). However, we have now found that regardless of mTORC1 activity, PGC-1α is not required for skeletal muscle remodeling via chronic overload.…”

“…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)(15)(16). Finally, a recently discovered transcript variant of PGC-1α called PGC-1α4 also protects against skeletal muscle wasting and even promotes skeletal muscle hypertrophy (17).…”

Potential therapeutic interventions for chronic kidney disease‐associated sarcopenia via indoxyl sulfate‐induced mitochondrial dysfunction

“…In fact, oxidative stress and inflammation cause the expression of the peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC‐1α), a master regulator for mitochondrial biosynthesis, to be reduced and to an increase in autophagy, a mitochondria degradation system. Interestingly, Brault et al demonstrated that the overexpression of PGC‐1α caused a resistance to muscle atrophy that was induced by denervation or fasting 11. Similarly, Wenz et al also showed that the overexpression of PGC‐1α in mice prevented muscle atrophy and hence extended their life span 12.…”

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

“…While endurance exercise induces PGC-1 as described above different experimental or pathological muscle wasting conditions like denervation-induced atrophy, statin treatment, diabetes, uremia, and cancer cachexia, reduce PGC-1 and/or PGC-1 levels [138][139][140][141]. Accordingly, ectopic expression of PGC-1 or PGC-1 counteracts the atrophic state by suppressing atrogenes in vitro and in vivo [140][141][142]. PGC-1 coactivators are thus able to preserve muscle structure and function under unfavorable circumstances.…”