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.

Control of skeletal muscle atrophy in response to disuse: clinical/preclinical contentions and fallacies of evidence

“…To test whether a reduction in spermine oxidase expression is required for muscle atrophy, we transfected mouse muscle fibers in vivo with plasmid encoding spermine oxidase under control of a constitutively active promoter, and then, in the presence of constitutive spermine oxidase expression, we applied muscle atrophy stimuli (immobilization, p21 overexpression, fasting, or denervation). We found that forced expression of spermine oxidase reduced skeletal muscle fiber atrophy caused by immobilization, p21 overexpression, fasting, and denervation, indicating that a reduction in spermine oxidase expression is at least partially required for muscle atrophy during these conditions (8). Taken together, these data identified spermine oxidase as an important factor in the maintenance of skeletal muscle mass and a key downstream target of p21 during immobilization and other atrophy conditions.…”

“…To determine whether a reduction in spermine oxidase might be sufficient to induce muscle atrophy, we used in vivo RNAi to knoc kdown spermine oxidase expression in healthy, nonimmobilized, wild-type skeletal muscle fibers. We found that spermine oxidase knockdown decreased skeletal muscle fiber size, indicating that a reduction in spermine oxidase is sufficient to induce muscle fiber atrophy (8). To test whether a reduction in spermine oxidase expression is required for muscle atrophy, we transfected mouse muscle fibers in vivo with plasmid encoding spermine oxidase under control of a constitutively active promoter, and then, in the presence of constitutive spermine oxidase expression, we applied muscle atrophy stimuli (immobilization, p21 overexpression, fasting, or denervation).…”

“…Surprisingly, a genome-wide analysis of the effects of p21 on mRNA expression in mouse skeletal muscle revealed that p21 strongly represses the mRNA encoding spermine oxidase, which was also the most strongly repressed mRNA in immobilized skeletal muscle (8). In addition, we found that 1) the reduction of spermine oxidase mRNA by immobilization or p21 expression was accompanied by reduction in spermine oxidase protein, 2) p21 knockdown in immobilized skeletal muscle not only reduced atrophy but also restored spermine oxidase expression, and 3) other muscle atrophy stimuli that increase skeletal muscle p21 expression (aging, fasting, and denervation) also decrease spermine oxidase mRNA and spermine oxidase protein (8).…”

“…The loss of load bearing in skeletal muscle is translated via currently undefined signaling pathway(s) (8) and results in a reduction in the rate of MPS, an increase in MPB, or most likely some degree of both (8,15). A recent exchange of ideas on whether it is a reduction in MPS or an increase in MPB that predominates (and is most effectively treated) resulting in disuse-induced atrophy has been published (14,16).…”

Blockade of Metallothioneins 1 and 2 Increases Skeletal Muscle Mass and Strength

“…We also found that ablation of metallothioneins increased the mRNA levels of spermine oxidase (Smox). A role for Smox in maintaining basal skeletal muscle gene expression and fiber size has recently been described, and Smox is strongly repressed under muscle catabolic conditions such as fasting, immobilization, and denervation (36). In contrast, forced overexpression of Smox partially prevented muscle fiber …”