Modulation of reactive oxygen species in skeletal muscle by myostatin is mediated through NF-κB
Open accessAbstract
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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Exercise-induced reduction of myostatin by irisin reduces availability of myostatin to engage in proinflammatory responses.
“Likewise, exercise-induced reduction of myostatin by irisin [44] (7a) was described to reduce availability of myostatin to engage in proinflammatory responses [116] (7b).”
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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
- PMC
- PMC5028794
- 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
- Update notices
- correction (2016-09-06)
- Open access
- bronze
- doi.org
- 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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