2. Academic Validation
  3. Superoxide is an intrinsic signaling molecule triggering muscle hypertrophy

Superoxide is an intrinsic signaling molecule triggering muscle hypertrophy

  • Antioxid Redox Signal. 2024 Jun 15. doi: 10.1089/ars.2024.0595.
Siyu Lu 1,  Yiming Zhou 2,  Mincong Liu 3,  Lijun Gong 4,  Li Liu 5,  Zhigui Duan 6,  Keke Chen 7,  Frank Gonzalez 8 9,  Fang Wei 10,  Rong Xiang 11,  Guolin Li 12
Affiliations

Affiliations

  • 1 Hunan Normal University, College of Life Sciences, Changsha, Hunan, China; 446034520@qq.com.
  • 2 Hunan Normal University, College of Life Sciences, Changsha, Hunan, China; 1148684338@qq.com.
  • 3 Hunan Normal University, College of Life Sciences, Changsha, Hunan, China; 2218943844@qq.com.
  • 4 Hunan Normal University, College of Life Sciences, Changsha, Hunan, China; 2944016950@qq.com.
  • 5 Hunan Normal University, College of Life Sciences, Changsha, Hunan, China; 1907263234@qq.com.
  • 6 Hunan Normal University, College of Life Sciences, Changsha, Hunan, China; zhiguiduan@hunnu.edu.cn.
  • 7 Hunan Normal University, College of Life Sciences, Changsha, Hunan, China; kekechen0819@163.com.
  • 8 NCI, LM, 37/3106, Bethesda, Maryland, United States, 20892.
  • 9 United States; gonzalef@mail.nih.gov.
  • 10 Hunan Normal University, College of Life Sciences, Changsha, Hunan, China; weifang2019@hunnu.edu.cn.
  • 11 Central South University, School of Life Sciences, Changsha, Hunan, China; shirlesmile@csu.edu.cn.
  • 12 Hunan Normal University, College of Life Sciences, Changsha, Hunan, China; hnsdlgl@hunnu.edu.cn.
PMID: 38877802 DOI: 10.1089/ars.2024.0595
Abstract

Aims: Redox signaling plays a key role in skeletal muscle remodeling induced by exercise and prolonged inactivity, but it is unclear which oxidant triggers myofiber hypertrophy due to the lack of strategies to precisely regulate individual oxidants in vivo. In this study, we used tetrathiomolybdate (TM) to dissociate the link between superoxide and H2O2 and thereby to specifically explore the role of superoxide in muscle hypertrophy in C2C12 cells and mice.

Results: TM can linearly regulate intracellular superoxide levels by inhibition of superoxide dismutase 1 (SOD1). A 70% increase in superoxide levels in C2C12 myoblast cells and mice is necessary and sufficient for triggering hypertrophy of differentiated myotubes, and can enhance exercise performance by more than 50% in mice. SOD1 knockout blocks TM-induced superoxide increments and thereby prevents hypertrophy, whereas SOD1 restoration rescues all these effects. Scavenging superoxide with antioxidants abolishes TM-induced hypertrophy and the enhancement of exercise performance, while the restoration of superoxide levels with a superoxide generator promotes muscle hypertrophy independent of SOD1 activity.

Innovation and conclusion: These findings suggest that superoxide is an endogenous initiator of myofiber hypertrophy, and that TM may be used to treat muscle wasting diseases. Our work not only suggests a novel druggable mechanism to increase muscle mass but also provides a tool for precisely regulating superoxide levels in vivo.

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