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
Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck 6020, Austria.
Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary.
Development. 2016 May 1;143(9):1547-59. doi: 10.1242/dev.129676. Epub 2016 Mar 10.
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.
骨骼肌兴奋-收缩（EC）偶联独立于钙内流。事实上，电压门控钙通道CaV1.1的可变剪接在成熟肌肉中可有效抑制钙电流。目前尚不清楚这对于肌肉的正常发育和功能是否必要。然而，导致钙传导性发育型CaV1.1e剪接变体异常表达的剪接缺陷与强直性肌营养不良中的肌肉无力相关。在此，我们删除了小鼠的CaV1.1（Cacna1s）外显子29。这些小鼠总体运动表现正常，尽管握力和自主跑步能力有所下降。成年小鼠中发育型CaV1.1e剪接变体的持续表达导致EC偶联期间钙内流增加、钙稳态改变以及分离的肌纤维中出现自发钙火花。收缩力降低而耐力增强。纤维类型特异性的关键调节因子失调，纤维类型组成向慢肌纤维转变。然而，氧化酶活性和线粒体含量下降。这些发现表明，在骨骼肌EC偶联过程中限制钙内流对于钙信号在纤维类型组成的活动依赖性调节中的次要功能以及预防肌肉疾病很重要。
