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

Sci Rep. 2017 Aug 31;7(1):10237. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Autophagy
  • Mice
  • Mice, Transgenic
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology*
  • Muscular Atrophy / genetics
  • Muscular Atrophy / metabolism
  • Muscular Atrophy / pathology*
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism*
  • Organ Size
  • Oxidative Stress
  • Proteolysis
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*
  • Ubiquitination

Substances

  • Nuclear Proteins
  • PGC1B protein, mouse
  • Transcription Factors