Failure to up-regulate transcription of genes necessary for muscle adaptation underlies limb girdle muscular dystrophy 2A (calpainopathy)
Failure to up-regulate transcription of genes necessary for muscle adaptation underlies limb girdle muscular dystrophy 2A (calpainopathy)
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DOI：
10.1093/hmg/ddw086
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发表时间：
2016-06-01
影响因子：
3.5
通讯作者：
Spencer, Melissa J.
中科院分区：
文献类型：
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作者：
Kramerova, Irina;Ermolova, Natalia;Spencer, Melissa J.
肢带型肌营养不良症2A是由于钙蛋白酶3(CAPN3)基因功能丧失突变所致。我们以前的数据表明，CAPN3有助于维持骨骼肌中三联体复合体的完整性。在Capn3基因敲除小鼠(C3KO)中，Ca~(2+)释放和Ca~(2+)/钙调蛋白激酶II(CaMKII)信号减弱。我们假设，钙化症可能是由于未能传递负荷诱导的钙离子介导的信号，而这是上调肌肉适应基因表达所必需的。为了验证这一假设，我们比较了野生型(WT)和C3KO小鼠在耐力运动中的肌肉转录。在WT小鼠中，运动诱导了一个基因签名，其中包括肌肉适应所必需的肌原纤维、线粒体和氧化脂肪代谢基因。C3KO肌肉无法激活相同的基因签名。此外，与异常转录图谱一致，我们观察到脂代谢的相应功能缺陷，即C3KO肌肉无法从储存的三酰甘油中释放脂肪酸。伴随着氧化代谢的缺陷，C3KO小鼠表现出运动耐力下降。未能上调C3KO肌肉中的基因，部分原因是PGC1α水平降低，这是一种协调肌肉适应反应的转录辅助调节因子。PGC1α的失稳可归因于通过CaMKII信号减弱而导致的p38MAPK活性降低。因此，我们阐明了钙离子介导的CaMKII激活下游的一条途径，该途径在C3KO小鼠中功能失调，导致参与肌肉适应的基因转录减少。这些研究确定了肌肉营养不良的一种新机制：对肌肉负荷的转录反应迟钝，导致慢性适应和重塑失败。
Limb girdle muscular dystrophy 2A is due to loss-of-function mutations in the Calpain 3 (CAPN3) gene. Our previous data suggest that CAPN3 helps to maintain the integrity of the triad complex in skeletal muscle. In Capn3 knock-out mice (C3KO), Ca2+ release and Ca2+/calmodulin kinase II (CaMKII) signaling are attenuated. We hypothesized that calpainopathy may result from a failure to transmit loading-induced Ca2+-mediated signals, necessary to up-regulate expression of muscle adaptation genes. To test this hypothesis, we compared transcriptomes of muscles from wild type (WT) and C3KO mice subjected to endurance exercise. In WT mice, exercise induces a gene signature that includes myofibrillar, mitochondrial and oxidative lipid metabolism genes, necessary for muscle adaptation. C3KO muscles fail to activate the same gene signature. Furthermore, in agreement with the aberrant transcriptional profile, we observe a commensurate functional defect in lipid metabolism whereby C3KO muscles fail to release fatty acids from stored triacylglycerol. In conjunction with the defects in oxidative metabolism, C3KO mice demonstrate reduced exercise endurance. Failure to up-regulate genes in C3KO muscles is due, in part, to decreased levels of PGC1 alpha, a transcriptional co-regulator that orchestrates the muscle adaptation response. Destabilization of PGC1 alpha is attributable to decreased p38 MAPK activation via diminished CaMKII signaling. Thus, we elucidate a pathway downstream of Ca2+-mediated CaMKII activation that is dysfunctional in C3KO mice, leading to reduced transcription of genes involved in muscle adaptation. These studies identify a novel mechanism of muscular dystrophy: a blunted transcriptional response to muscle loading resulting in chronic failure to adapt and remodel.