Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume 1803, Issue 8, Pages 960-967Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamcr.2010.03.019
Keywords
Skeletal muscle; Atrophy; Calcineurin; PGC-1 alpha; Diabetes; Streptozotocin
Categories
Funding
- National Institutes of Health [DK61521, DK50740, DK066422]
- Department of Veterans Affairs
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PGC-1 alpha is a transcriptional coactivator that controls energy homeostasis through regulation of glucose and oxidative metabolism. Both PGC-1 alpha expression and oxidative capacity are decreased in skeletal muscle of patients and animals undergoing atrophy, suggesting that PGC-1 alpha participates in the regulation of muscle mass. PGC-1 alpha gene expression is controlled by calcium- and cAMP-sensitive pathways. However, the mechanism regulating PGC-1 alpha in skeletal muscle during atrophy remains unclear. Therefore, we examined the mechanism responsible for decreased PGC-1 alpha expression using a rodent streptozotocin (STZ) model of chronic diabetes and atrophy. After 21 days, the levels of PGC-1 alpha protein and mRNA were decreased. We examined the activation state of CREB, a potent activator of PGC-1 alpha transcription, and found that phospho-CREB was paradoxically high in muscle of STZ-rats, suggesting that the cAMP pathway was not involved in PGC-1 alpha regulation. In contrast expression of calcineurin (Cn), a calcium-dependent phosphatase, was suppressed in the same muscles. PGC-1 alpha expression is regulated by two Cn substrates, MEF2 and NFATc Therefore, we examined MEF2 and NFATc activity in muscles from STZ-rats. Target genes MRF4 and MCIP1.4 mRNAs were both significantly reduced, consistent with reduced Cn signaling. Moreover, levels of MRF4, MCIP1.4, and PGC-1 alpha were also decreased in muscles of CnA alpha(-/-) and CnA beta(-/-) mice without diabetes indicating that decreased Cn signaling, rather than changes in other calcium- or cAMP-sensitive pathways, were responsible for decreased PGC-1 alpha expression. These findings demonstrate that Cn activity is a major determinant of PGC-1 alpha expression in skeletal muscle during diabetes and possibly other conditions associated with loss of muscle mass. Published by Elsevier B.V.
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