Muscle Disuse Atrophy Caused by Discord of Intracellular Signaling

Li Li Ji, Dongwook Yeo, Choung-Hun Kang

Research output: Contribution to journalReview articlepeer-review

9 Scopus citations


Significance: Regular contractile activity plays a critical role in maintaining skeletal muscle morphological integrity and physiological function. If the muscle is forced to stop contraction, such as during limb immobilization (IM), the IGF/Akt/mTOR signaling pathway that normally stimulates protein synthesis and inhibits proteolysis will be suppressed, whereas the FoxO-controlled catabolic pathways such as ubiquitin-proteolysis and autophagy/mitophagy will be activated and dominate, resulting in muscle fiber atrophy. Recent Advances: Mitochondria occupy a central position in the regulation of both protein synthesis and degradation through several redox-sensitive pathways, including peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), mitochondrial fusion and fission proteins, mitophagy, and sirtuins. Prolonged IM downregulates PGC-1α due to AMPK (5′-AMP-activated protein kinase) and FoxO activation, thus decreasing mitochondrial biogenesis and causing oxidative damage. Decrease of mitochondrial inner membrane potential and increase of mitochondrial fission can trigger cascades of mitophagy leading to loss of mitochondrial homeostasis (mitostasis), inflammation, and apoptosis. The phenotypic outcomes of these disorders are compromised muscle function and fiber atrophy. Critical Issues: Given the molecular mechanism of the pathogenesis, it is imperative that the integrity of intracellular signaling be restored to prevent the deterioration. So far, overexpression of PGC-1α via transgene and in vivo DNA transfection has been found to be effective in ameliorating mitostasis and reduces IM-induced muscle atrophy. Nutritional supplementation of select amino acids and phytochemicals also provides mechanistic and practical insights into the prevention of muscle disuse atrophy. Future Directions: In light of the importance of mitochondria in regulating the various critical signaling pathways, future work should focus on exploring new epigenetic strategies to restore mitostasis and redox balance.

Original languageEnglish (US)
Pages (from-to)727-744
Number of pages18
JournalAntioxidants and Redox Signaling
Issue number11
Early online dateApr 28 2020
StatePublished - Oct 10 2020

Bibliographical note

Funding Information:
This work was supported in part by a grant-in-aid by the University of Minnesota Office of the Vice President for Research.

Publisher Copyright:
© Copyright 2020, Mary Ann Liebert, Inc., publishers 2020.


  • PGC-1α
  • atrophy
  • mitochondria
  • proteolysis
  • redox signaling
  • skeletal muscle

PubMed: MeSH publication types

  • Journal Article


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