title: Skeletal Muscle Regeneration and Oxidative Stress Are Altered in Chronic Kidney Disease.
abstract: Skeletal muscle atrophy and impaired muscle function are associated with lower health-related quality of life, and greater disability and mortality risk in those with chronic kidney disease (CKD). However, the pathogenesis of skeletal dysfunction in CKD is unknown. We used a slow progressing, naturally occurring, CKD rat model (Cy/+ rat) with hormonal abnormalities consistent with clinical presentations of CKD to study skeletal muscle signaling. The CKD rats demonstrated augmented skeletal muscle regeneration with higher activation and differentiation signals in muscle cells (i.e. lower Pax-7; higher MyoD and myogenin RNA expression). However, there was also higher expression of proteolytic markers (Atrogin-1 and MuRF-1) in CKD muscle relative to normal. CKD animals had higher indices of oxidative stress compared to normal, evident by elevated plasma levels of an oxidative stress marker, 8-hydroxy-2' -deoxyguanosine (8-OHdG), increased muscle expression of succinate dehydrogenase (SDH) and Nox4 and altered mitochondria morphology. Furthermore, we show significantly higher serum levels of myostatin and expression of myostatin in skeletal muscle of CKD animals compared to normal. Taken together, these data show aberrant regeneration and proteolytic signaling that is associated with oxidative stress and high levels of myostatin in the setting of CKD. These changes likely play a role in the compromised skeletal muscle function that exists in CKD.
authors.affiliation: Department of Physical Therapy, Indiana University School of Health and Rehabilitation Sciences, Indianapolis, IN, United States of America.|Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Keith G
authors.identifier: http://orcid.org/0000-0001-9426-7862
authors.initials: KG
authors.lastname: Avin
authors.affiliation: Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Neal X
authors.initials: NX
authors.lastname: Chen
authors.affiliation: Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Organ
authors.affiliation: Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Chad
authors.initials: C
authors.lastname: Zarse
authors.affiliation: Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Kalisha
authors.initials: K
authors.lastname: O'Neill
authors.affiliation: Lilly Research laboratories, Eli Lilly and Company, Indianapolis, IN, United States of America.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Conway
authors.affiliation: Lilly Research laboratories, Eli Lilly and Company, Indianapolis, IN, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Konrad
authors.affiliation: Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Bacallao
authors.affiliation: Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Allen
authors.affiliation: Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Moe
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D055435:Myostatin / Q000097:blood* / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D012038:Regeneration; D051436:Renal Insufficiency, Chronic / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction
chemical_list: C525913:Mstn protein, rat; D055435:Myostatin