title: Modulation of reactive oxygen species in skeletal muscle by myostatin is mediated through NF-κB.
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.
authors.affiliation: Department of Genomics and Genetics, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Sriram
authors.forename: Subha
authors.initials: S
authors.lastname: Subramanian
authors.forename: Durga
authors.initials: D
authors.lastname: Sathiakumar
authors.forename: Rithika
authors.initials: R
authors.lastname: Venkatesh
authors.forename: Monica S
authors.initials: MS
authors.lastname: Salerno
authors.forename: Craig D
authors.initials: CD
authors.lastname: McFarlane
authors.forename: Ravi
authors.initials: R
authors.lastname: Kambadur
authors.forename: Mridula
authors.initials: M
authors.lastname: Sharma
mesh_terms: D000375:Aging; D000818:Animals; D000975:Antioxidants / Q000378:metabolism* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000009:adverse effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D055435:Myostatin / Q000172:deficiency / Q000235:genetics; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D061251:Primary Cell Culture; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D055948:Sarcopenia / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000975:Antioxidants; D055435:Myostatin; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D046988:Proteasome Endopeptidase Complex