Aberrant calcium influx causes fiber type shift and mitochondrial loss in skeletal muscle

Skeletal muscle excitation-contraction (EC) coupling is independent of calcium influx. In fact alternative splicing of the voltage-gated calcium channel CaV1.1 actively suppresses calcium currents in mature muscle. Why this might be necessary is not known. However, splicing defects causing aberrant expression of the calcium-conducting embryonic CaV1.1e splice variant correlate with muscle weakness in myotonic dystrophy. Here we deleted CaV1.1 exon 29 in mice. The continued expression of CaV1.1e resulted in increased calcium influx during EC coupling and spontaneous calcium sparks. While overall motor performance was normal, muscle force was reduced, endurance enhanced, and the fiber type composition shifted toward slower fibers. In contrast, oxidative enzyme activity and the mitochondrial content declined. Together with the dysregulation of key regulators of the slow program these findings indicate that limiting calcium influx during skeletal muscle EC coupling is important for the calcium signal’s secondary function in the activity-dependent regulation of fiber type composition. Differential gene expression between soleus and EDL muscle fibres from wildtype and Cav1.1 delta E29 mice.