Calcineurin is necessary for the maintenance but not embryonic development of slow muscle fibers.
Skeletal muscles are a mosaic of slow and fast twitch myofibers. During embryogenesis, patterns of fiber type composition are initiated that change postnatally to meet physiological demand. To examine the role of the protein phosphatase calcineurin in the initiation and maintenance of muscle fiber types, we used a "Flox-ON" approach to obtain muscle-specific overexpression of the modulatory calcineurin-interacting protein 1 (MCIP1/DSCR1), an inhibitor of calcineurin. Myo-Cre transgenic mice with early skeletal muscle-specific expression of Cre recombinase were used to activate the Flox-MCIP1 transgene. Contractile components unique to type 1 slow fibers were absent from skeletal muscle of adult Myo-Cre/Flox-MCIP1 mice, whereas oxidative capacity, myoglobin content, and mitochondrial abundance were unaltered. The soleus muscles of Myo-Cre/Flox-MCIP1 mice fatigued more rapidly than the wild type as a consequence of the replacement of the slow myosin heavy chain MyHC-1 with a fast isoform, MyHC-2A. MyHC-1 expression in Myo-Cre/Flox-MCIP1 embryos and early neonates was normal. These results demonstrate that developmental patterning of slow fibers is independent of calcineurin, while the maintenance of the slow-fiber phenotype in the adult requires calcineurin activity.
Oh
Misook
M
University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.
Rybkin
Igor I
II
Copeland
Victoria
V
Czubryt
Michael P
MP
Shelton
John M
JM
van Rooij
Eva
E
Richardson
James A
JA
Hill
Joseph A
JA
De Windt
Leon J
LJ
Bassel-Duby
Rhonda
R
Olson
Eric N
EN
Rothermel
Beverly A
BA
D000818:Animals; D019703:Calcineurin / Q000502:physiology*; D003285:Contractile Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins; D047108:Embryonic Development / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000201:enzymology; D018657:Muscle Fibers, Slow-Twitch / Q000201:enzymology*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000196:embryology / Q000201:enzymology*; D009211:Myoglobin / Q000378:metabolism
D003285:Contractile Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D009211:Myoglobin; C108612:RCAN1 protein, human; D019703:Calcineurin