Mitochondrial dysfunction and consequences in calpain-3-deficient muscle.
Mitochondrial dysfunction and consequences in calpain-3-deficient muscle.
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DOI：
10.1186/s13395-020-00254-1
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发表时间：
2020-12-11
期刊：
影响因子：
4.9
通讯作者：
Nagaraju K
中科院分区：
文献类型：
--
作者：
Jahnke VE;Peterson JM;Van Der Meulen JH;Boehler J;Uaesoontrachoon K;Johnston HK;Defour A;Phadke A;Yu Q;Jaiswal JK;Nagaraju K
非溶酶体半胱氨酸蛋白酶 calpain-3 的无义突变或功能丧失突变会导致 2A 型肢带型肌营养不良症 (LGMD2A)。虽然 calpain-3 与肌肉细胞分化、肌节形成和肌肉细胞骨架重塑有关，但 LGMD2A 的生理学基础仍然难以捉摸。使用健康小鼠和 calpain-3 缺陷小鼠建立的肌肉和肌肉细胞培养物分析细胞生长、基因表达谱以及线粒体含量和功能。 Calpain-3 缺陷小鼠还接受 PPAR-δ 激动剂 (GW501516) 治疗，以评估线粒体功能和膜修复。未配对 t 检验用于评估两组或治疗之间观察到的差异的显着性。方差分析用于评估随时间变化的显着性。我们发现 calpain-3 缺乏会导致肌肉和成肌细胞线粒体功能障碍。 Calpain-3 缺陷的成肌细胞显示增殖增加，其基因表达谱显示异常的线粒体生物发生。肌管基因表达分析进一步揭示了 calpain-3 缺陷肌肉中脂质代谢的改变。线粒体缺陷在体外和体内得到验证。我们使用 GW501516 来改善 7 个月大 calpain-3 缺陷小鼠的体内线粒体生物发生。 MyoD 和 Pax7 mRNA 表达增加表明这种治疗改善了卫星细胞活性。它还降低了肌肉疲劳性并降低了血清肌酸激酶水平。线粒体功能下降还损害了缺乏 calpain-3 的骨骼肌的肌膜修复。通过急性丙酮酸治疗改善线粒体活性，改善肌膜修复。我们的结果提供了证据，表明骨骼肌中的 calpain-3 缺乏与线粒体生物发生和功能不良有关，导致肌膜修复不良。通过改善线粒体活性的药物来解决这一缺陷，为 LGMD2A 提供了新的治疗途径。
Nonsense or loss-of-function mutations in the non-lysosomal cysteine protease calpain-3 result in limb-girdle muscular dystrophy type 2A (LGMD2A). While calpain-3 is implicated in muscle cell differentiation, sarcomere formation, and muscle cytoskeletal remodeling, the physiological basis for LGMD2A has remained elusive. Cell growth, gene expression profiling, and mitochondrial content and function were analyzed using muscle and muscle cell cultures established from healthy and calpain-3-deficient mice. Calpain-3-deficient mice were also treated with PPAR-delta agonist (GW501516) to assess mitochondrial function and membrane repair. The unpaired t test was used to assess the significance of the differences observed between the two groups or treatments. ANOVAs were used to assess significance over time. We find that calpain-3 deficiency causes mitochondrial dysfunction in the muscles and myoblasts. Calpain-3-deficient myoblasts showed increased proliferation, and their gene expression profile showed aberrant mitochondrial biogenesis. Myotube gene expression analysis further revealed altered lipid metabolism in calpain-3-deficient muscle. Mitochondrial defects were validated in vitro and in vivo. We used GW501516 to improve mitochondrial biogenesis in vivo in 7-month-old calpain-3-deficient mice. This treatment improved satellite cell activity as indicated by increased MyoD and Pax7 mRNA expression. It also decreased muscle fatigability and reduced serum creatine kinase levels. The decreased mitochondrial function also impaired sarcolemmal repair in the calpain-3-deficient skeletal muscle. Improving mitochondrial activity by acute pyruvate treatment improved sarcolemmal repair. Our results provide evidence that calpain-3 deficiency in the skeletal muscle is associated with poor mitochondrial biogenesis and function resulting in poor sarcolemmal repair. Addressing this deficit by drugs that improve mitochondrial activity offers new therapeutic avenues for LGMD2A.
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影响因子：
4.9
作者：
Jahnke VE;Van Der Meulen JH;Johnston HK;Ghimbovschi S;Partridge T;Hoffman EP;Nagaraju K
通讯作者：
Nagaraju K
影响因子：
30.8
作者：
Irwin, WA;Bergamin, N;Bonaldo, P
通讯作者：
Bonaldo, P
影响因子：
3.7
作者：
Duguez, S;Sabido, O;Freyssenet, D
通讯作者：
Freyssenet, D
影响因子：
5.3
作者：
Franko, Andras;Mayer, Sabine;Goffart, Steffi
通讯作者：
Goffart, Steffi
影响因子：
1.2
作者：
Defour, Aurelia;Sreetama, S. C.;Jaiswal, Jyoti K.
通讯作者：
Jaiswal, Jyoti K.