PGC-1α protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription

Abstract

Maintaining muscle size and fiber composition requires contractile activity. Increased activity stimulates expression of the transcriptional coactivator PGC-1␣ (peroxisome proliferator-activated receptor ␥ coactivator 1␣), which promotes fiber-type switching from glycolytic toward more oxidative fibers. In response to disuse or denervation, but also in fasting and many systemic diseases, muscles undergo marked atrophy through a common set of transcriptional changes. FoxO family transcription factors play a critical role in this loss of cell protein, and when activated, FoxO3 causes expression of the atrophy-related ubiquitin ligases atrogin-1 and MuRF-1 and profound loss of muscle mass. To understand how exercise might retard muscle atrophy, we investigated the possible interplay between PGC-1␣ and the FoxO family in regulation of muscle size. Rodent muscles showed a large decrease in PGC-1␣ mRNA during atrophy induced by denervation as well as by cancer cachexia, diabetes, and renal failure. Furthermore, in transgenic mice overexpressing PGC-1␣, denervation and fasting caused a much smaller decrease in muscle fiber diameter and a smaller induction of atrogin-1 and MuRF-1 than in control mice. Increased expression of PGC-1␣ also increased mRNA for several genes involved in energy metabolism whose expression decreases during atrophy. Transfection of PGC-1␣ into adult fibers reduced the capacity of FoxO3 to cause fiber atrophy and to bind to and transcribe from the atrogin-1 promoter. Thus, the high levels of PGC-1␣ in dark and exercising muscles can explain their resistance to atrophy, and the rapid fall in PGC-1␣ during atrophy should enhance the FoxO-dependent loss of muscle mass.denervation ͉ fasting ͉ muscle fiber ͉ energy metabolism ͉ mitochondria

Age associated low mitochondrial biogenesis may be explained by lack of response of PGC-1α to exercise training

“…PGC-1α protects against skeletal muscle atrophy ( Sandri et al 2006) and very recently it has been shown to be required for training-induced prevention of age associated decline in mitochondria (Leick et al 2010). Moreover, relevance of PGC-1α in sarcopenia and metabolic diseases during aging has been also suggested (Wenz et al 2009).…”

“…PGC-1α is currently identified as a new therapeutic target for treatment of age-related mitochondrial dysfunction in skeletal muscle, and more generally for sarcopenia (Sandri et al 2006). Moreover, recently, an interesting paper has underpinned the critical role of PGC-1α to link nuclear and mitcochondrial changes in aging (Kelly 2011).…”

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

“…Moreover, pathogenesis of neurodegenerative disorders such as Parkinson's, Alzheimer's, or Huntington's disease is generally related to an abnormal ubiquitin‐proteasome mechanism as either a primary cause or secondary consequence (Ciechanover & Brundin, 2003; Kikis et al ., 2010; Webb & Brunet, 2014). FOXOs act on both the upregulation of ubiquitin ligases and by controlling the composition of the proteasome (Bodine et al ., 2001; Sandri et al ., 2004, 2006; Stitt et al ., 2004; Vilchez et al ., 2012). However, the direct effect of FOXO‐mediated proteostasis in mammals remains to be understood.…”

“…Foxo3 has been shown to be a transcriptional regulator of muscle‐specific E3 ubiquitin ligases, which are major effectors of protein degradation in muscle (Sandri et al ., 2004, 2006; Stitt et al ., 2004). But FOXOs can also affect the composition of the proteasome.…”

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

“…Importantly, in line with the mitochondrial decline, PGC‐1α expression decreases during muscle aging in different species, including humans (Ghosh et al., 2011; Kang, Chung, Diffee, & Ji, 2013; Short et al., 2005; Vina et al., 2009). Moreover, PGC‐1α improves various muscle disorders, for example, denervation‐induced fiber atrophy (Sandri et al., 2006) or Duchenne muscular dystrophy (Handschin, Kobayashi et al., 2007). Of note, conclusions about the function of PGC‐1α in the context of natural aging are difficult to extrapolate from premature aging models, for example, those with severe mitochondrial impairment.…”