title: Myostatin induces DNA damage in skeletal muscle of streptozotocin-induced type 1 diabetic mice.
abstract: One of the features of uncontrolled type 1 diabetes is oxidative stress that induces DNA damage and cell death. Skeletal muscle atrophy is also considerable in type 1 diabetes, however, the signaling mechanisms that induce oxidative stress culminating in muscle atrophy are not fully known. Here, we show that in Streptozotocin-induced diabetic wild type mice, hypo-phosphorylation of Akt, resulted in activation of Foxa2 transcription factor in the muscle. Foxa2 transcriptionally up-regulated Myostatin, contributing to exaggerated oxidative stress leading to DNA damage via p63/REDD1 pathway in skeletal muscle of Streptozotocin-treated wild type mice. In Myostatin(-/-) mice however, Streptozotocin treatment did not reduce Akt phosphorylation despite reduced IRS-1 signaling. Moreover, Foxa2 levels remained unaltered in Myostatin(-/-) mice, while levels of p63/REDD1 were higher compared with wild type mice. Consistent with these results, relatively less DNA damage and muscle atrophy was observed in Myostatin(-/-) muscle in response to Streptozotocin treatment. Taken together, our results for the first time show the role of Foxa2 in Myostatin regulation in skeletal muscle in diabetic mice. Altogether, these results demonstrate the mechanism by which Myostatin contributes to DNA damage in skeletal muscle of the diabetic mice that would lead to myofiber degeneration.
authors.affiliation: From the Division of Molecular Genetics and Cell Biology, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Sriram
authors.forename: Subha
authors.initials: S
authors.lastname: Subramanian
authors.forename: Prasanna Kumar
authors.initials: PK
authors.lastname: Juvvuna
authors.forename: Craig
authors.initials: C
authors.lastname: McFarlane
authors.forename: Monica Senna
authors.initials: MS
authors.lastname: Salerno
authors.forename: Ravi
authors.initials: R
authors.lastname: Kambadur
authors.forename: Mridula
authors.initials: M
authors.lastname: Sharma
mesh_terms: D000818:Animals; D002460:Cell Line; D004249:DNA Damage; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology; D055435:Myostatin / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C469992:Ddit4 protein, mouse; C496503:Foxa2 protein, mouse; C525912:Mstn protein, mouse; D055435:Myostatin; D010750:Phosphoproteins; D015534:Trans-Activators; D014157:Transcription Factors; C486419:Trp63 protein, mouse; D051542:Hepatocyte Nuclear Factor 3-beta; D051057:Proto-Oncogene Proteins c-akt
keywords: DNA; DNA Damage; Diabetes; Myostatin; Skeletal Muscle; Type 1 Diabetes; p63