Cited by 189Muscle Physiology and DisordersExercise and Physiological ResponsesNutrition and Health in Aging

Modulation of reactive oxygen species in skeletal muscle by myostatin is mediated through NF-κB

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Sriram, Sandhya, Subramanian, Subha, Sathiakumar, Durga, Venkatesh, Rithika, Salerno, Monica S., McFarlane, Craig D., Kambadur, Ravi, Sharma, Mridula·2011·Aging Cell

Abstract

Abnormal levels of reactive oxygen species (ROS) and inflammatory cytokines have been observed in the skeletal muscle during muscle wasting including sarcopenia. However, the mechanisms that signal ROS production and prolonged maintenance of ROS levels during muscle wasting are not fully understood. Here, we show that myostatin (Mstn) is a pro-oxidant and signals the generation of ROS in muscle cells. Myostatin, a transforming growth factor-β (TGF-β) family member, has been shown to play an important role in skeletal muscle wasting by increasing protein degradation. Our results here show that Mstn induces oxidative stress by producing ROS in skeletal muscle cells through tumor necrosis factor-α (TNF-α) signaling via NF-κB and NADPH oxidase. Aged Mstn null (Mstn(-/-) ) muscles, which display reduced sarcopenia, also show an increased basal antioxidant enzyme (AOE) levels and lower NF-κB levels indicating efficient scavenging of excess ROS. Additionally, our results indicate that both TNF-α and hydrogen peroxide (H(2) O(2) ) are potent inducers of Mstn and require NF-κB signaling for Mstn induction. These results demonstrate that Mstn and TNF-α are components of a feed forward loop in which Mstn triggers the generation of second messenger ROS, mediated by TNF-α and NADPH oxidase, and the elevated TNF-α in turn stimulates Mstn expression. Higher levels of Mstn in turn induce muscle wasting by activating proteasomal-mediated catabolism of intracellular proteins. Thus, we propose that inhibition of ROS induced by Mstn could lead to reduced muscle wasting during sarcopenia.

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Crossref · 10.1111/j.1474-9726.2011.00734.x

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Authors
Sriram, S., Subramanian, S., Sathiakumar, D., Venkatesh, R., Salerno, M. S., McFarlane, C. D., Kambadur, R., & Sharma, M.
Affiliations
  • Nanyang Technological University (SG)
  • Singapore Institute for Clinical Sciences (SG)
  • National University of Singapore (SG)
Corresponding author
Sharma, Mridula
Venue
Aging Cell
Publisher
Wiley
Published
2011-08-16
Volume
10
Issue
6
Pages
931-948
ISSN
  • 1474-9718 (ISSN-L)
  • 1474-9726
OpenAlex
W1659590378
Cited by
189
References
60
Citations by year
2026: 6 · 2025: 12 · 2024: 13 · 2023: 12 · 2022: 13 · 2021: 20 · 2020: 14 · 2019: 9 · 2018: 17 · 2017: 10 · 2016: 17 · 2015: 15 · 2014: 9 · 2013: 16 · 2012: 5
FWCI
4.02
Type
journal article
Language
en
Open access
Locations
  • Aging Cell (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • ResearchOnline - JCU (James Cook University) (submittedVersion)
Funders
  • National Research Foundation
  • National Research Foundation Singapore
  • Ministry of Education - Singapore
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
  • Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
Keywords
myostatin, reactive oxygen species, skeletal muscle atrophy, sarcopenia, NF-κB signaling, TNF-α, NADPH oxidase, oxidative stress, hydrogen peroxide, feed-forward loop, antioxidant enzymes, Mstn knockout mice
MeSH terms
Aging, Animals, Antioxidants, Humans, Hydrogen Peroxide, Male, Mice, Inbred C57BL, Tumor Necrosis Factor-alpha, Signal Transduction, Transforming Growth Factor beta, NF-kappa B, Reactive Oxygen Species, Mice, Knockout, Oxidative Stress, Muscle, Skeletal, NADPH Oxidases, Proteasome Endopeptidase Complex, Cell Proliferation, Mice, Myostatin, Sarcopenia, Proteolysis, Primary Cell Culture

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