Acute failure of action potential conduction in mdx muscle reveals new mechanism of contraction-induced force loss
Acute failure of action potential conduction in mdx muscle reveals new mechanism of contraction-induced force loss
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DOI：
10.1113/jphysiol.2013.254656
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发表时间：
2013-08-01
影响因子：
5.5
通讯作者：
Lowe, Dawn A.
中科院分区：
文献类型：
--
作者：
Call, Jarrod A.;Warren, Gordon L.;Lowe, Dawn A.
缺乏肌营养不良蛋白的骨骼肌的一个主要特征是对收缩引起的力量丧失高度敏感，如Duchenne肌营养不良症。我们测试了一种假设，即广泛的力量丧失是由于质膜电生理功能的损害，特别是损害了动作电位的发展。来自MDX和野生型小鼠的前脚部肌肉在体内进行了一次100次电刺激的偏心收缩。分析肌肉收缩时的肌电图，特别是M波，以评估胫骨前肌浆膜产生和传导动作电位的能力。在偏心收缩中，野生型小鼠的踝关节扭矩损失了36%，而mdx小鼠表现出更大的扭矩损失，为73%(P<；0.001)。尽管扭矩损失，野生型小鼠的M波均方根值没有下降，这与mdx鼠的M波均方根值下降了55%形成了鲜明对比(P<；0.001)。这种损伤在24小时内消失，并与强度和膜完整性的显著改善相一致。对未损伤和损伤的指长伸肌进行静息膜电位(RMP)的细胞内测量，以确定是否发生了慢性去极化，这可能导致纤维兴奋性受损和/或动作电位传导特性改变。野生型未损伤细胞和损伤细胞的RMP分布差异无统计学意义(中位数：-73.2mV比-72.7mV，P=0.001)，而MDX未损伤细胞和损伤细胞的分布差异有统计学意义(中位数：-71.5mV和-56.6mV，P<0.001)。这些数据表明，MDX肌肉纤维在一轮破坏性的偏心收缩后去极化。这些发现(I)提示了Duchenne肌营养不良症收缩所致损伤的主要基于质膜的力量丧失机制与健康肌肉截然不同，(Ii)表明dystrophin对维持偏心收缩后动作电位的产生和传导至关重要。
A primary feature of skeletal muscle lacking the protein dystrophin, as occurring in Duchenne muscular dystrophy, is a hypersensitivity to contraction-induced strength loss. We tested the hypothesis that the extensive strength loss results from an impairment in the electrophysiological function of the plasmalemma specifically impaired action potential development. Anterior crural muscles from mdx and wildtype mice performed a single bout of 100 electrically stimulated eccentric contractions in vivo. Electromyography, specifically the M-wave, was analysed during muscle contraction to assess the ability of the tibialis anterior muscle plasmalemma to generate and conduct action potentials. During eccentric contractions, wildtype mice exhibited a 36% loss in torque about the ankle but mdx mice exhibited a greater torque loss of 73% (P < 0.001). Despite the loss of torque, there was no reduction in M-wave root mean square (RMS) for wildtype mice, which was in stark contrast to mdx mice that had a 55% reduction in M-wave RMS (P < 0.001). This impairment resolved within 24 h and coincided with a significant improvement in strength and membrane integrity. Intracellular measurements of resting membrane potential (RMP) in uninjured and injured extensor digitorum longus muscles were made to determine if a chronic depolarization had occurred, which could lead to impaired fibre excitability and/or altered action potential conduction properties. The distributions of RMP were not different between wildtype uninjured and injured muscle cells (median: -73.2 mV vs. -72.7 mV, P= 0.46) whereas there was a significant difference between mdx uninjured and injured cells (median: -71.5 mV vs. -56.6 mV, P < 0.001). These data show that mdx muscle fibres are depolarized after an injurious bout of eccentric contractions. These findings (i) suggest a major plasmalemma-based mechanism of strength loss underlying contraction-induced injury in Duchenne muscular dystrophy distinctly different from that for healthy muscle, and (ii) demonstrate dystrophin is critical for maintaining action potential generation and conduction after eccentric contractions.