Long-term PGC1\u03b2 overexpression leads to apoptosis, autophagy and muscle wasting

Danesh H Sopariwala,Sabina Lorca,Pierre-Marie Badin,Isabelle K Vila,Min Sup Song,Vihang A Narkar,Eun Ran Kim,Qingchun Tong,Megha Sheth,George G Rodney,Neah Likhite,Vikas Yadav

doi:10.1038/s41598-017-10238-9

Abstract

Skeletal muscle wasting is prevalent in many chronic diseases, necessitating inquiries into molecular regulation of muscle mass. Nuclear receptor co-activator peroxisome proliferator-activated receptor co-activator 1 alpha (PGC1α) and its splice variant PGC1α4 increase skeletal muscle mass. However, the effect of the other PGC1 sub-type, PGC1β, on muscle size is unclear. In transgenic mice selectively over-expressing PGC1β in the skeletal muscle, we have found that PGC1β progressively decreases skeletal muscle mass predominantly associated with loss of type 2b fast-twitch myofibers. Paradoxically, PGC1β represses the ubiquitin-proteolysis degradation pathway genes resulting in ubiquitinated protein accumulation in muscle. However, PGC1β overexpression triggers up-regulation of apoptosis and autophagy genes, resulting in robust activation of these cell degenerative processes, and a concomitant increase in muscle protein oxidation. Concurrently, PGC1β up-regulates apoptosis and/or autophagy transcriptional factors such as E2f1, Atf3, Stat1, and Stat3, which may be facilitating myopathy. Therefore, PGC1β activation negatively affects muscle mass over time, particularly fast-twitch muscles, which should be taken into consideration along with its known aerobic effects in the skeletal muscle.

Highlights

Aging and other chronic diseases including cancer, diabetes, obesity, and chronic obstructive pulmonary disease (COPD) lead to severe muscle wasting, affecting mobility and overall health[1,2,3]
PGC1β induces a battery of master-transcriptional factors including E2F transcription factor 1 (E2f1), transformation related protein 53 (Trp53), activating transcription factor 3 (Atf3), and signal transducer and activator of transcription (Stat) 1, 2 and 3, which are known to be associated with apoptosis and muscle wasting[22,23,24,25]
In PGC1β-TG compared to WT mice, the protein levels of PGC1β were ~5 fold higher in fast twitch muscles and 1.7 fold higher in the soleus, while expression in the heart was not affected

Summary

Introduction

Aging and other chronic diseases including cancer, diabetes, obesity, and chronic obstructive pulmonary disease (COPD) lead to severe muscle wasting, affecting mobility and overall health[1,2,3]. Apoptosis is activated in myofibers by cellular stress, injury and impaired mitochondrial function leading to muscle loss[5, 6]. As much as ubiquitin-proteasome degradation, apoptosis, and autophagy are established cellular phenomenon associated with muscle homeostasis, the transcriptional regulators that orchestrate these pathways remain to be fully defined. Transient overexpression of PGC1β in muscle by electroporation protects against denervation induced muscle wasting by inhibiting ubiquitin-mediated proteolysis[20]. We investigate the potential role of PGC1β in the regulation of skeletal muscle mass and the related gene network it activates. The loss of muscle mass is associated with oxidative stress and activation of the gene program leading to apoptosis and autophagy-mediated loss of myofibers. PGC1β induces a battery of master-transcriptional factors including E2F transcription factor 1 (E2f1), transformation related protein 53 (Trp53), activating transcription factor 3 (Atf3), and signal transducer and activator of transcription (Stat) 1, 2 and 3, which are known to be associated with apoptosis and muscle wasting[22,23,24,25]

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Results

Conclusion