Long-term PGC1β overexpression leads to apoptosis, autophagy and muscle wasting

• Published in: Scientific reports Vol. 7; no. 1; p. 10237
• Main Authors: Sopariwala, Danesh H., Yadav, Vikas, Badin, Pierre-Marie, Likhite, Neah, Sheth, Megha, Lorca, Sabina, Vila, Isabelle K., Kim, Eun Ran, Tong, Qingchun, Song, Min Sup, Rodney, George G., Narkar, Vihang A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31-08-2017; Nature Publishing Group
• Subjects: 13/2; 38/39; 631/443/319/1557; 64; 64/110; 692/4017; 82/1; 82/51; Activating transcription factor 3; Alternative splicing; Animals; Apoptosis; Autophagy; Cell activation; Chronic illnesses; Humanities and Social Sciences; Life Sciences; Mice; Mice, Transgenic; multidisciplinary; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscles; Muscular Atrophy - genetics; Muscular Atrophy - metabolism; Muscular Atrophy - pathology; Musculoskeletal system; Myopathy; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Organ Size; Oxidation; Oxidative Stress; Phagocytosis; Proteolysis; Rodents; Science; Science (multidisciplinary); Skeletal muscle; Stat1 protein; Stat3 protein; Transcription activation; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transgenic mice; Ubiquitin; Ubiquitination
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-10238-9

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.