title: Spermine oxidase maintains basal skeletal muscle gene expression and fiber size and is strongly repressed by conditions that cause skeletal muscle atrophy.
abstract: Skeletal muscle atrophy is a common and debilitating condition that remains poorly understood at the molecular level. To better understand the mechanisms of muscle atrophy, we used mouse models to search for a skeletal muscle protein that helps to maintain muscle mass and is specifically lost during muscle atrophy. We discovered that diverse causes of muscle atrophy (limb immobilization, fasting, muscle denervation, and aging) strongly reduced expression of the enzyme spermine oxidase. Importantly, a reduction in spermine oxidase was sufficient to induce muscle fiber atrophy. Conversely, forced expression of spermine oxidase increased muscle fiber size in multiple models of muscle atrophy (immobilization, fasting, and denervation). Interestingly, the reduction of spermine oxidase during muscle atrophy was mediated by p21, a protein that is highly induced during muscle atrophy and actively promotes muscle atrophy. In addition, we found that spermine oxidase decreased skeletal muscle mRNAs that promote muscle atrophy (e.g., myogenin) and increased mRNAs that help to maintain muscle mass (e.g., mitofusin-2). Thus, in healthy skeletal muscle, a relatively low level of p21 permits expression of spermine oxidase, which helps to maintain basal muscle gene expression and fiber size; conversely, during conditions that cause muscle atrophy, p21 expression rises, leading to reduced spermine oxidase expression, disruption of basal muscle gene expression, and muscle fiber atrophy. Collectively, these results identify spermine oxidase as an important positive regulator of muscle gene expression and fiber size, and elucidate p21-mediated repression of spermine oxidase as a key step in the pathogenesis of skeletal muscle atrophy.
authors.affiliation: Departments of Internal Medicine and Molecular Physiology and Biophysics and Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine.
authors.forename: Kale S
authors.initials: KS
authors.lastname: Bongers
authors.affiliation: Departments of Internal Medicine and Molecular Physiology and Biophysics and Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Fox
authors.affiliation: Departments of Internal Medicine and Molecular Physiology and Biophysics and Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Kunkel
authors.affiliation: College of Pharmacy, Roy J. and Lucille A. Carver College of Medicine.
authors.forename: Larissa V
authors.initials: LV
authors.lastname: Stebounova
authors.affiliation: College of Pharmacy, Roy J. and Lucille A. Carver College of Medicine.
authors.forename: Daryl J
authors.initials: DJ
authors.lastname: Murry
authors.affiliation: Department of Biochemistry, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, and.
authors.forename: Miles A
authors.initials: MA
authors.lastname: Pufall
authors.affiliation: Departments of Internal Medicine and Molecular Physiology and Biophysics and Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Ebert
authors.affiliation: Departments of Internal Medicine and Molecular Physiology and Biophysics and Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Dyle
authors.affiliation: Departments of Internal Medicine and Molecular Physiology and Biophysics and Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, Iowa City Veterans Affairs Medical Center, Iowa City, Iowa.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Bullard
authors.affiliation: Departments of Internal Medicine and Molecular Physiology and Biophysics and Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Dierdorff
authors.affiliation: Departments of Internal Medicine and Molecular Physiology and Biophysics and Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, Iowa City Veterans Affairs Medical Center, Iowa City, Iowa christopher-adams@uiowa.edu.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Adams
mesh_terms: D000818:Animals; D005215:Fasting / Q000502:physiology; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009121:Muscle Denervation; D018485:Muscle Fibers, Skeletal / Q000201:enzymology / Q000378:metabolism*; D009133:Muscular Atrophy / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D018008:Myogenin / Q000235:genetics / Q000378:metabolism*; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012149:Restraint, Physical / Q000502:physiology; D000097667:Polyamine Oxidase
chemical_list: D020558:GTP Phosphohydrolases; D018008:Myogenin; D000587:Oxidoreductases Acting on CH-NH Group Donors; D012333:RNA, Messenger; D000097667:Polyamine Oxidase; C488751:Mfn2 protein, mouse
keywords: p21; polyamine; skeletal muscle; skeletal muscle atrophy; spermine oxidase