Protein kinase D1 stimulates MEF2 activity in skeletal muscle and enhances muscle performance.
Skeletal muscle consists of type I and type II myofibers, which exhibit different metabolic and contractile properties. Type I fibers display an oxidative metabolism and are resistant to fatigue, whereas type II fibers are primarily glycolytic and suited for rapid bursts of activity. These properties can be modified by changes in workload, activity, and hormonal stimuli, facilitating muscle adaptation to physiological demand. The MEF2 transcription factor promotes the formation of slow-twitch (type I) muscle fibers in response to activity. MEF2 activity is repressed by class II histone deacetylases (HDACs) and is enhanced by calcium-regulated protein kinases that promote the export of class II HDACs from the nucleus to the cytoplasm. However, the identities of skeletal muscle class II HDAC kinases are not well defined. Here we demonstrate that protein kinase D1 (PKD1), a highly effective class II HDAC kinase, is predominantly expressed in type I myofibers and, when misexpressed in type II myofibers, promotes transformation to a type I, slow-twitch, fatigue-resistant phenotype. Conversely, genetic deletion of PKD1 in type I myofibers increases susceptibility to fatigue. PKD1 cooperates with calcineurin to facilitate slow-twitch-fiber transformation. These findings identify PKD1 as a key regulator of skeletal muscle function and phenotype.
Kim
Mi-Sung
MS
Department of Molecular Biology, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.
Fielitz
Jens
J
McAnally
John
J
Shelton
John M
JM
Lemon
Douglas D
DD
McKinsey
Timothy A
TA
Richardson
James A
JA
Bassel-Duby
Rhonda
R
Olson
Eric N
EN
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D017353:Gene Deletion; D064326:MEF2 Transcription Factors; D051379:Mice; D008822:Mice, Transgenic; D018763:Muscle Fatigue / Q000235:genetics; D018657:Muscle Fibers, Slow-Twitch / Q000201:enzymology / Q000502:physiology; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000502:physiology*; D018006:Myogenic Regulatory Factors / Q000378:metabolism*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D064326:MEF2 Transcription Factors; D009124:Muscle Proteins; D018006:Myogenic Regulatory Factors; C089212:protein kinase D; D011493:Protein Kinase C; D019703:Calcineurin