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.骨骼肌兴奋-收缩（EC）偶联并不依赖钙内流。事实上，电压门控钙通道CaV1.1的可变剪接会主动抑制成熟肌肉中的钙电流，其必要性目前尚不明确。不过，导致钙通透性胚胎型CaV1.1e剪接变体异常表达的剪接缺陷，与肌强直性肌营养不良患者的肌无力症状相关。本研究在小鼠体内敲除了CaV1.1的外显子29；持续表达CaV1.1e会导致EC偶联过程中钙内流增加，并出现自发性钙火花。尽管整体运动表现正常，但小鼠的肌力下降、耐力提升，且肌纤维类型组成向慢肌纤维偏移。与之相反，其氧化酶活性与线粒体含量均有所降低。结合慢肌程序关键调控因子的失调情况，上述研究结果表明，在骨骼肌EC偶联过程中限制钙内流，对于钙信号在肌纤维类型组成的活性依赖性调控中所发挥的次级功能至关重要。本数据集包含野生型与Cav1.1 ΔE29小鼠的比目鱼肌及趾长伸肌（EDL）肌纤维的差异基因表达数据。