Matrix metalloproteinase-2 expression and promoter/enhancer activity in skeletal muscle atrophy.

Abstract

Matrix metalloproteinase-2 (MMP-2) appears to be the dominant MMP activated during skeletal muscle atrophy. However, little is known about cell-specific regulatory mechanisms of MMP-2 transcription in vivo. In this study, we used a mouse model of muscle atrophy induced by complete Achilles tendon transection. Time-dependent muscle weight loss, nuclei density reduction, and extracellular matrix degeneration were observed consistently after Achilles tendon transection. Increased MMP-2 expression was confirmed at the mRNA and protein level. Experiments using transgenic mice with a MMP-2 promoter/enhancer reporter construct demonstrated markedly increased MMP-2 promoter/enhancer activity in atrophic skeletal muscle. Tissue-specific upregulation of MMP-2 promoter activity was observed not only in myocytes, but also in blood vessels, nerve, and fascia. The transcription factors c-Jun and FosB were expressed at high levels in atrophic muscle, suggesting a role in MMP-2 upregulation. These findings show that increased MMP-2 activity in disused atrophic muscle and supporting tissues is regulated, at least in part, by increased MMP-2 promoter/enhancer activity.