title: Chronic kidney disease induces autophagy leading to dysfunction of mitochondria in skeletal muscle.
abstract: Chronic kidney disease (CKD) causes loss of lean body mass by multiple mechanisms. This study examines whether autophagy-mediated proteolysis contributes to CKD-induced muscle wasting. We tested autophagy in the muscle of CKD mice with plantaris muscle overloading to mimic resistance exercise or with acupuncture plus low-frequency electrical stimulation (Acu/LFES) treatment. In CKD muscle, Bnip3, Beclin-1, and LC3II mRNAs and proteins were increased compared with those in control muscle, indicating autophagosome-lysosome formation induction. Acu/LFES suppressed the CKD-induced upregulation of autophagy. However, overloading increased autophagy-related proteins in normal and CKD muscle. Serum from uremic mice induces autophagy formation but did not increase the myosin degradation or actin break down in cultured muscle satellite cells. We examined mitochondrial biogenesis, copy number, and ATP production in cultured myotubes, and found all three aspects to be decreased by uremic serum. Inhibition of autophagy partially reversed this decline in cultured myotubes. In CKD mice, the mitochondrial copy number, biogenesis marker peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), mitochondrial transcription factor A (TFAM), and mitochondrial fusion marker Mitofusin-2 (Mfn2) are decreased. Both muscle overloading and Acu/LFES increased mitochondrial copy number, and reversed the CKD-induced decreases in PGC-1α, TFAM, and Mfn2. We conclude that the autophagy is activated in the muscle of CKD mice. However, myofibrillar protein is not directly broken down through autophagy. Instead, CKD-induced upregulation of autophagy leads to dysfunction of mitochondria and decrease of ATP production.
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.|Renal Division, Department of Medicine, Emory University, Atlanta, Georgia.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Su
authors.affiliation: Renal Division, Department of Medicine, Emory University, Atlanta, Georgia.
authors.forename: Janet D
authors.initials: JD
authors.lastname: Klein
authors.affiliation: The Key Laboratory of Remodeling-related Cardiovascular Diseases, Beijing Anzhen Hospital Affiliated with Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.affiliation: Renal Division, Department of Medicine, Emory University, Atlanta, Georgia.
authors.forename: Harold A
authors.initials: HA
authors.lastname: Franch
authors.affiliation: Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, Texas; and.
authors.forename: Liping
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Renal Division, Department of Medicine, Emory University, Atlanta, Georgia.
authors.forename: Faten
authors.initials: F
authors.lastname: Hassounah
authors.affiliation: Department of Kinesiology, Temple University, Philadelphia, Pennsylvania.|Renal Division, Department of Medicine, Emory University, Atlanta, Georgia.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Hudson
authors.affiliation: Renal Division, Department of Medicine, Emory University, Atlanta, Georgia xwang03@emory.edu.
authors.forename: Xiaonan H
authors.initials: XH
authors.lastname: Wang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D000071186:Beclin-1 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000378:metabolism / Q000473:pathology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009133:Muscular Atrophy / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001678:Organelle Biogenesis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000150:complications*; D014511:Uremia / Q000097:blood
chemical_list: C508686:BNip3 protein, mouse; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; C480860:Map1lc3b protein, mouse; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; C081930:Tfam protein, mouse; D000255:Adenosine Triphosphate; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human
keywords: FoxO; LC3II; acidification; forkhead transcription factors; overloading; ubiquitin-proteasome system