Altered excitation-contraction coupling with skeletal muscle specific FKBP12 deficiency.
The immunophilin FKBP12 binds the skeletal muscle Ca2+ release channel or ryanodine receptor (RyR1), but the functional consequences of this interaction are not known. In this study, we have generated skeletal muscle specific FKBP12-deficient mice to investigate the role of FKBP12 in skeletal muscle. Primary myotubes from these mice show no obvious change in either Ca2+ stores or resting Ca2+ levels but display decreased voltage-gated intracellular Ca2+ release and increased L-type Ca2+ currents. Consistent with the decreased voltage-gated Ca2+ release, maximal tetanic force production is decreased and the force frequency curves are shifted to the right in extensor digitorum longus (EDL) muscles of the mutant mice. In contrast, there is no decrease in maximal tetanic force production in the mutant diaphragm or soleus muscle. The force frequency curve is shifted to the left in the FKBP12-deficient diaphragm muscle compared with controls. No changes in myosin heavy chain (MHC) phenotype are observed in EDL or soleus muscle of the FKBP12-deficient mice, but diaphragm muscle displays an increased ratio of slow to fast MHC isoforms. Also, calcineurin levels are increased in the diaphragm of the mutant mice but not in the soleus or EDL. In summary, FKBP12 deficiency alters both orthograde and retrograde coupling between the L-type Ca2+ channel and RyR1 and the consequences of these changes depend on muscle type and activity. In highly used muscles such as the diaphragm, adaptation to the loss of FKBP12 occurs, possibly due to the increased Ca2+ influx.
Tang
Wei
W
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
Ingalls
Christopher P
CP
Durham
William J
WJ
Snider
Jessica
J
Reid
Michael B
MB
Wu
Gangyi
G
Matzuk
Martin M
MM
Hamilton
Susan L
SL
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D003964:Diaphragm / Q000378:metabolism; D004553:Electric Conductivity; D005260:Female; D017353:Gene Deletion; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000235:genetics / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000502:physiology*; D018995:Myosin Heavy Chains; D010641:Phenotype; D024744:Skeletal Muscle Myosins; D022061:Tacrolimus Binding Protein 1A / Q000172:deficiency* / Q000235:genetics; D015854:Up-Regulation
D020746:Calcium Channels, L-Type; D019703:Calcineurin; D024744:Skeletal Muscle Myosins; D018995:Myosin Heavy Chains; D022061:Tacrolimus Binding Protein 1A; D002118:Calcium