Restricting calcium currents is required for correct fiber type specification in skeletal muscle

• Published in: Development (Cambridge) Vol. 143; no. 9; pp. 1547 - 1559
• Main Authors: Sultana, Nasreen, Dienes, Beatrix, Benedetti, Ariane, Tuluc, Petronel, Szentesi, Peter, Sztretye, Monika, Rainer, Johannes, Hess, Michael W, Schwarzer, Christoph, Obermair, Gerald J, Csernoch, Laszlo, Flucher, Bernhard E
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 01-05-2016
• Subjects: Action Potentials - physiology; Alternative Splicing - genetics; Animals; Calcium - metabolism; Calcium Channels, L-Type - genetics; Excitation Contraction Coupling - genetics; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Fibers, Fast-Twitch - cytology; Muscle Fibers, Fast-Twitch - physiology; Muscle Fibers, Slow-Twitch - cytology; Muscle Fibers, Slow-Twitch - physiology; Muscle Weakness - genetics; Muscle Weakness - metabolism; Muscle, Skeletal - embryology; Protein Isoforms - genetics; Muscle fiber type specification; Mouse; Voltage-gated calcium channel; Skeletal muscle excitation-contraction coupling
• ISSN: 0950-1991; 1477-9129
• DOI: 10.1242/dev.129676

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. Whether this is necessary for normal development and function of muscle is not known. However, splicing defects that cause aberrant expression of the calcium-conducting developmental CaV1.1e splice variant correlate with muscle weakness in myotonic dystrophy. Here, we deleted CaV1.1 (Cacna1s) exon 29 in mice. These mice displayed normal overall motor performance, although grip force and voluntary running were reduced. Continued expression of the developmental CaV1.1e splice variant in adult mice caused increased calcium influx during EC coupling, altered calcium homeostasis, and spontaneous calcium sparklets in isolated muscle fibers. Contractile force was reduced and endurance enhanced. Key regulators of fiber type specification were dysregulated and the fiber type composition was shifted toward slower fibers. However, oxidative enzyme activity and mitochondrial content declined. These findings indicate that limiting calcium influx during skeletal muscle EC coupling is important for the secondary function of the calcium signal in the activity-dependent regulation of fiber type composition and to prevent muscle disease.