Key result
JP2-S165F mutation increases resting Ca2+ and myotube diameter while impairing excitation-contraction coupling gain.
Why the study?
The effects of JP2 mutations associated with hypertrophic cardiomyopathy on skeletal muscle function and Ca2+ signalling have not been examined.
The JP2-S165F mutation, which is associated with human hypertrophic cardiomyopathy, induces hypertrophy and alters intracellular Ca2+ signaling in skeletal muscle.
JP2-S165F may induce skeletal muscle hypertrophy via Ca2+ dysregulation; leaves open cardiac translation in human HCM.
JPs (junctophilins) contribute to the formation of junctional membrane complexes in muscle cells by physically linking the t-tubule (transverse-tubule) and SR (sarcoplasmic reticulum) membranes. In humans with HCM (hypertrophic cardiomyopathy), mutations in JP2 are linked to altered Ca2+ signalling in cardiomyocytes; however, the effects of these mutations on skeletal muscle function have not been examined. In the present study, we investigated the role of the dominant-negative JP2-S165F mutation (which is associated with human HCM) in skeletal muscle. Consistent with the hypertrophy observed in human cardiac muscle, overexpression of JP2-S165F in primary mouse skeletal myotubes led to a significant increase in myotube diameter and resting cytosolic Ca2+ concentration. Single myotube Ca2+ imaging experiments showed reductions in both the excitation-contraction coupling gain and RyR (ryanodine receptor) 1-mediated Ca2+ release from the SR. Immunoprecipitation assays revealed defects in the PKC (protein kinase C)-mediated phosphorylation of the JP2-S165F mutant protein at Ser165 and in binding of JP2-S165F to the Ca2+ channel TRPC3 (transient receptor potential cation canonical-type channel 3) on the t-tubule membrane. Therefore both the hypertrophy and altered intracellular Ca2+ signalling in the JP2-S165F-expressing skeletal myotubes can be linked to altered phosphorylation of JP2 and/or altered cross-talk among Ca2+ channels on the t-tubule and SR membranes.
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Woo et al. (2010) studied Hypertrophic cardiomyopathy. Overexpression of JP2-S165F mutation was evaluated on Myotube diameter and resting cytosolic Ca2+ concentration. Overexpression of the JP2-S165F mutation in primary mouse skeletal myotubes increased myotube diameter and resting cytosolic Ca2+ concentration, and reduced excitation-contraction coupling gain.
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