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Spermine oxidase maintains basal skeletal muscle gene expression and fiber size and is strongly repressed by conditions that cause skeletal muscle atrophy
Journal article   Open access

Spermine oxidase maintains basal skeletal muscle gene expression and fiber size and is strongly repressed by conditions that cause skeletal muscle atrophy

Kale S Bongers, Daniel K Fox, Steven D Kunkel, Larissa V Stebounova, Daryl J Murry, Miles A Pufall, Scott M Ebert, Michael C Dyle, Steven A Bullard, Jason M Dierdorff, …
American journal of physiology: endocrinology and metabolism, Vol.308(2), pp.E144-E158
01/15/2015
DOI: 10.1152/ajpendo.00472.2014
PMCID: PMC4297781
PMID: 25406264
url
https://doi.org/10.1152/ajpendo.00472.2014View
Published (Version of record) Open Access

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.
 Muscular Atrophy - metabolism Fasting - physiology Mice, Inbred C57BL RNA, Messenger - genetics Restraint, Physical - physiology Muscle Denervation Oxidoreductases Acting on CH-NH Group Donors - genetics Immunoblotting Male Muscular Atrophy - genetics Myogenin - genetics Oxidoreductases Acting on CH-NH Group Donors - metabolism Gene Expression Regulation, Enzymologic - physiology Muscle Fibers, Skeletal - metabolism Muscular Atrophy - enzymology Animals GTP Phosphohydrolases - metabolism GTP Phosphohydrolases - genetics RNA, Messenger - chemistry Mice Real-Time Polymerase Chain Reaction Myogenin - metabolism Muscle Fibers, Skeletal - enzymology

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