Long-term PGC1β overexpression leads to apoptosis, autophagy and muscle wasting.
Danesh H SopariwalaVikas YadavPierre-Marie BadinNeah LikhiteMegha ShethSabina LorcaIsabelle K VilaEun Ran KimQingchun TongMin Sup SongGeorge G RodneyVihang A NarkarPublished in: Scientific reports (2017)
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.
Keyphrases
- skeletal muscle
- endoplasmic reticulum stress
- insulin resistance
- oxidative stress
- cell death
- cell proliferation
- signaling pathway
- transcription factor
- cell cycle arrest
- genome wide
- immune response
- gene expression
- binding protein
- adipose tissue
- mesenchymal stem cells
- inflammatory response
- nuclear factor
- single cell
- nitric oxide
- early onset
- stem cells
- muscular dystrophy
- genome wide identification