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Compensatory regulation of HDAC5 in muscle maintains metabolic adaptive responses and metabolism in response to energetic stress
Author(s) -
McGee Sean L.,
Swinton Courtney,
Morrison Shona,
Gaur Vidhi,
Campbell Duncan E.,
Jorgensen Sebastian B.,
Kemp Bruce E.,
Baar Keith,
Steinberg Gregory R.,
Hargreaves M.
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-249359
Subject(s) - histone deacetylase 5 , biology , protein kinase a , kinase , phosphorylation , microbiology and biotechnology , histone deacetylase , biochemistry , histone , gene
Some gene deletions or mutations have little effect on metabolism and metabolic adaptation because of redundancy and/or compensation in metabolic pathways. The mechanisms for redundancy and/ or compensation in metabolic adaptation in mammalian cells are unidentified. Here, we show that in mouse muscle and myogenic cells, compensatory regulation of the histone deacetylase (HDAC5) transcriptional repressor maintains metabolic integrity. HDAC5 phosphorylation regulated the expression of diverse metabolic genes and glucose metabolism in mouse C2C12 myogenic cells. However, loss of AMP‐activated protein kinase (AMPK), a HDAC5 kinase, in muscle did not affect HDAC5 phosphorylation in mouse skeletal muscle during exercise, but resulted in a compensatory increase (32.6%) in the activation of protein kinase D (PKD), an alternate HDAC5 kinase. Constitutive PKD activation in mouse C2C12 myogenic cells regulated metabolic genes and glucose metabolism. Although aspects of this response were HDAC5 phosphorylation dependent, blocking HDAC5 phosphorylation when PKD was active engaged an alternative compensatory adaptive mechanism, which involved post‐transcriptional reductions in HDAC5 mRNA (–93.1%) and protein. This enhanced the expression of a specific subset of metabolic genes and mitochondrial metabolism. These data show that compensatory regulation of HDAC5 maintains metabolic integrity in mammalian cells and reinforces the importance of preserving the cellular metabolic adaptive response.—McGee, S. L., Swinton, C., Morrison, S., Gaur, V., Campbell, D. E., Jorgensen, S. B., Kemp, B. E., Baar, K., Steinberg, G. R., Hargreaves, M. Compensatory regulation of HDAC5 in muscle maintains metabolic adaptive responses and metabolism in response to energetic stress. FASEB J. 28, 3384–3395 (2014). www.fasebj.org