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, Christopher M. Adams

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Spermine oxidase maintains basal skeletal muscle gene expression and fiber size and is strongly repressed by conditions that cause skeletal muscle atrophy. Am J Physiol Endocrinol Metab 308: E144-E158, 2015. First published November 18, 2014; doi:10.1152/ajpendo.00472.2014.-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.

Original languageEnglish (US)
Pages (from-to)E144-E158
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume308
Issue number2
DOIs
StatePublished - Jan 15 2015

Fingerprint

Muscular Atrophy
Skeletal Muscle Fibers
Skeletal Muscle
Gene Expression
Muscles
polyamine oxidase
Immobilization
Fasting
Muscle Denervation
Myogenin
Messenger RNA
Muscle Proteins
Denervation
Regulator Genes

Keywords

  • Polyamine
  • Skeletal muscle
  • Skeletal muscle atrophy
  • Spermine oxi-dase
  • p21

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

Cite this

Spermine oxidase maintains basal skeletal muscle gene expression and fiber size and is strongly repressed by conditions that cause skeletal muscle atrophy. / Bongers, Kale S.; Fox, Daniel K.; Kunkel, Steven D.; Stebounova, Larissa V.; Murry, Daryl J; Pufall, Miles A.; Ebert, Scott M.; Dyle, Michael C.; Bullard, Steven A.; Dierdorff, Jason M.; Adams, Christopher M.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 308, No. 2, 15.01.2015, p. E144-E158.

Research output: Contribution to journalArticle

Bongers, Kale S. ; Fox, Daniel K. ; Kunkel, Steven D. ; Stebounova, Larissa V. ; Murry, Daryl J ; Pufall, Miles A. ; Ebert, Scott M. ; Dyle, Michael C. ; Bullard, Steven A. ; Dierdorff, Jason M. ; Adams, Christopher M. / Spermine oxidase maintains basal skeletal muscle gene expression and fiber size and is strongly repressed by conditions that cause skeletal muscle atrophy. In: American Journal of Physiology - Endocrinology and Metabolism. 2015 ; Vol. 308, No. 2. pp. E144-E158.
@article{f9e46c2fb87345e29ded10fb06613d84,
title = "Spermine oxidase maintains basal skeletal muscle gene expression and fiber size and is strongly repressed by conditions that cause skeletal muscle atrophy",
abstract = "Spermine oxidase maintains basal skeletal muscle gene expression and fiber size and is strongly repressed by conditions that cause skeletal muscle atrophy. Am J Physiol Endocrinol Metab 308: E144-E158, 2015. First published November 18, 2014; doi:10.1152/ajpendo.00472.2014.-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.",
keywords = "Polyamine, Skeletal muscle, Skeletal muscle atrophy, Spermine oxi-dase, p21",
author = "Bongers, {Kale S.} and Fox, {Daniel K.} and Kunkel, {Steven D.} and Stebounova, {Larissa V.} and Murry, {Daryl J} and Pufall, {Miles A.} and Ebert, {Scott M.} and Dyle, {Michael C.} and Bullard, {Steven A.} and Dierdorff, {Jason M.} and Adams, {Christopher M.}",
year = "2015",
month = "1",
day = "15",
doi = "10.1152/ajpendo.00472.2014",
language = "English (US)",
volume = "308",
pages = "E144--E158",
journal = "American Journal of Physiology - Renal Physiology",
issn = "0363-6127",
publisher = "American Physiological Society",
number = "2",

}

TY - JOUR

T1 - Spermine oxidase maintains basal skeletal muscle gene expression and fiber size and is strongly repressed by conditions that cause skeletal muscle atrophy

AU - Bongers, Kale S.

AU - Fox, Daniel K.

AU - Kunkel, Steven D.

AU - Stebounova, Larissa V.

AU - Murry, Daryl J

AU - Pufall, Miles A.

AU - Ebert, Scott M.

AU - Dyle, Michael C.

AU - Bullard, Steven A.

AU - Dierdorff, Jason M.

AU - Adams, Christopher M.

PY - 2015/1/15

Y1 - 2015/1/15

N2 - Spermine oxidase maintains basal skeletal muscle gene expression and fiber size and is strongly repressed by conditions that cause skeletal muscle atrophy. Am J Physiol Endocrinol Metab 308: E144-E158, 2015. First published November 18, 2014; doi:10.1152/ajpendo.00472.2014.-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.

AB - Spermine oxidase maintains basal skeletal muscle gene expression and fiber size and is strongly repressed by conditions that cause skeletal muscle atrophy. Am J Physiol Endocrinol Metab 308: E144-E158, 2015. First published November 18, 2014; doi:10.1152/ajpendo.00472.2014.-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.

KW - Polyamine

KW - Skeletal muscle

KW - Skeletal muscle atrophy

KW - Spermine oxi-dase

KW - p21

UR - http://www.scopus.com/inward/record.url?scp=84921485242&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84921485242&partnerID=8YFLogxK

U2 - 10.1152/ajpendo.00472.2014

DO - 10.1152/ajpendo.00472.2014

M3 - Article

VL - 308

SP - E144-E158

JO - American Journal of Physiology - Renal Physiology

JF - American Journal of Physiology - Renal Physiology

SN - 0363-6127

IS - 2

ER -