title: Ulk1-mediated autophagy plays an essential role in mitochondrial remodeling and functional regeneration of skeletal muscle.
abstract: Autophagy is a conserved cellular process for degrading aggregate proteins and dysfunctional organelle. It is still debatable if autophagy and mitophagy (a specific process of autophagy of mitochondria) play important roles in myogenic differentiation and functional regeneration of skeletal muscle. We tested the hypothesis that autophagy is critical for functional regeneration of skeletal muscle. We first observed time-dependent increases (3- to 6-fold) of autophagy-related proteins (Atgs), including Ulk1, Beclin1, and LC3, along with reduced p62 expression during C2C12 differentiation, suggesting increased autophagy capacity and flux during myogenic differentiation. We then used cardiotoxin (Ctx) or ischemia-reperfusion (I/R) to induce muscle injury and regeneration and observed increases in Atgs betweendays 2and7in adult skeletal muscle followed by increased autophagy flux afterday 7Since Ulk1 has been shown to be essential for mitophagy, we asked if Ulk1 is critical for functional regeneration in skeletal muscle. We subjected skeletal muscle-specificUlk1knockout mice (MKO) to Ctx or I/R. MKO mice had significantly impaired recovery of muscle strength and mitochondrial protein content post-Ctx or I/R. Imaging analysis showed that MKO mice have significantly attenuated recovery of mitochondrial network at 7 and 14 days post-Ctx. These findings suggest that increased autophagy protein and flux occur during muscle regeneration and Ulk1-mediated mitophagy is critical for recovery for the mitochondrial network and hence functional regeneration.
authors.affiliation: Department of Medicine, University of Virginia, Charlottesville, Virginia.|Center for Skeletal Muscle Research at Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia; and.
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Call
authors.affiliation: Department of Medicine, University of Virginia, Charlottesville, Virginia.|Center for Skeletal Muscle Research at Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia; and.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Wilson
authors.affiliation: Department of Medicine, University of Virginia, Charlottesville, Virginia.|Center for Skeletal Muscle Research at Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia; and.
authors.forename: Rhianna C
authors.initials: RC
authors.lastname: Laker
authors.affiliation: Department of Medicine, University of Virginia, Charlottesville, Virginia.|Center for Skeletal Muscle Research at Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia; and.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Mondira
authors.initials: M
authors.lastname: Kundu
authors.affiliation: Department of Medicine, University of Virginia, Charlottesville, Virginia; zhen.yan@virginia.edu.|Department of Pharmacology, University of Virginia, Charlottesville, Virginia.|Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia.|Center for Skeletal Muscle Research at Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia; and.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D000071189:Autophagy-Related Protein-1 Homolog / Q000172:deficiency / Q000235:genetics*; D000071186:Beclin-1 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004179:Cobra Cardiotoxin Proteins / Q000633:toxicity; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D063306:Mitophagy / Q000187:drug effects / Q000502:physiology*; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D032448:Myoblasts, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012038:Regeneration / Q000187:drug effects / Q000502:physiology*; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000071456:Sequestosome-1 Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000071186:Beclin-1; C115010:Becn1 protein, mouse; D004179:Cobra Cardiotoxin Proteins; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D000071189:Autophagy-Related Protein-1 Homolog; C112444:Ulk1 protein, mouse
keywords: Unc-51-like autophagy activating kinase 1; mitophagy; muscle repair; torque