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Abstract：
What is the central question of this study? Does fukutin deficiency in skeletal muscle cause mitochondrial dysfunction, and if so, can AMP-activated protein kinase (AMPK) stimulation via 5-aminoimidazole-4-carboxamide ribonucleotide attenuate this through regulation of mitochondrial biogenesis and autophagy? What is the main finding and its importance? Mitochondrial dysfunction is associated with fukutin deficiency and AMPK stimulation may benefit muscle contractility to a greater extent than mitochondrial function.
Disruptions in the dystrophin-glycoprotein complex (DGC) are clearly the primary basis underlying various forms of muscular dystrophies and dystroglycanopathies, but the cellular consequences of DGC disruption are still being investigated. Mitochondrial abnormalities are becoming an apparent consequence and contributor to dystrophy disease pathology. Herein, we demonstrate that muscle-specific deletion of the fukutin gene (Myf5/fktn-KO mice (Fktn KO)), a model of secondary dystroglycanopathy, results in ∼30% lower muscle strength (P < 0.001) and 16% lower mitochondrial respiratory function (P = 0.002) compared to healthy littermate controls (LM). We also observed ∼80% lower expression of the gene for peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) (P = 0.004), a primary transcription factor for mitochondrial biogenesis, in Fktn KO mice that likely contributes to the mitochondrial defects. PGC-1α is post-translationally regulated via phosphorylation by AMP-activated protein kinase (AMPK). Treatment with the AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) failed to rescue mitochondrial deficits in Fktn KO mice (P = 0.458) but did have beneficial (∼30% greater) effects on recovery of muscle contractility following injury in both LM and Fktn KO mice compared to saline treatment (P = 0.006). The beneficial effects of AMPK stimulation via AICAR on muscle contractile function may be partially explained by AMPK\'s other role of regulating skeletal muscle autophagy, a cellular process critical for clearance of damaged and/or dysfunctional organelles. Two primary conclusions can be drawn from this data: (1) fukutin deletion produces intrinsic muscular metabolic defects that likely contribute to dystroglycanopathy disease pathology, and (2) AICAR treatment accelerates recovery of muscle contractile function following injury suggesting AMPK signalling as a possible target for therapeutic strategies.
Disruptions in the dystrophin-glycoprotein complex (DGC) are clearly the primary basis underlying various forms of muscular dystrophies and dystroglycanopathies, but the cellular consequences of DGC disruption are still being investigated. Mitochondrial abnormalities are becoming an apparent consequence and contributor to dystrophy disease pathology. Herein, we demonstrate that muscle-specific deletion of the fukutin gene (Myf5/fktn-KO mice (Fktn KO)), a model of secondary dystroglycanopathy, results in ∼30% lower muscle strength (P < 0.001) and 16% lower mitochondrial respiratory function (P = 0.002) compared to healthy littermate controls (LM). We also observed ∼80% lower expression of the gene for peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) (P = 0.004), a primary transcription factor for mitochondrial biogenesis, in Fktn KO mice that likely contributes to the mitochondrial defects. PGC-1α is post-translationally regulated via phosphorylation by AMP-activated protein kinase (AMPK). Treatment with the AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) failed to rescue mitochondrial deficits in Fktn KO mice (P = 0.458) but did have beneficial (∼30% greater) effects on recovery of muscle contractility following injury in both LM and Fktn KO mice compared to saline treatment (P = 0.006). The beneficial effects of AMPK stimulation via AICAR on muscle contractile function may be partially explained by AMPK\'s other role of regulating skeletal muscle autophagy, a cellular process critical for clearance of damaged and/or dysfunctional organelles. Two primary conclusions can be drawn from this data: (1) fukutin deletion produces intrinsic muscular metabolic defects that likely contribute to dystroglycanopathy disease pathology, and (2) AICAR treatment accelerates recovery of muscle contractile function following injury suggesting AMPK signalling as a possible target for therapeutic strategies.
摘要：
这项研究的核心问题是什么？如果是这样,通过5-氨基咪唑-4-甲酰胺核糖核苷酸刺激AMP激活的蛋白激酶（AMPK）可以通过调节线粒体生物发生和自噬来减弱这种情况吗？主要发现及其重要性是什么？
肌营养不良蛋白-糖蛋白复合物（DGC）的破坏显然是各种形式的肌营养不良和营养不良症的主要基础。但是DGC破坏的细胞后果仍在研究中。线粒体异常正在成为营养不良疾病病理的明显后果和贡献者。在这里，我们证明了fukutin基因的肌肉特异性缺失（Myf5/fktn-KO小鼠（FktnKO）），继发性营养不良的模型，结果与健康同窝对照（LM）相比，肌肉力量降低了30％（P<0.001），线粒体呼吸功能降低了16％（P=0.002）。我们还观察到过氧化物酶体增殖物激活受体-γ共激活因子1α（PGC-1α）基因的表达降低了80％（P=0.004），线粒体生物发生的主要转录因子，在FktnKO小鼠中，可能导致线粒体缺陷。PGC-1α通过AMP激活的蛋白激酶（AMPK）的磷酸化进行翻译后调节。使用AMPK激动剂5-氨基咪唑-4-甲酰胺核糖核苷酸（AICAR）治疗未能挽救FktnKO小鼠的线粒体缺陷（P=0.458），但确实对恢复肌肉收缩性有益（〜30％以上）与盐水治疗相比，LM和FktnKO小鼠受伤后的收缩力（P=0.006）。通过AICAR刺激AMPK对肌肉收缩功能的有益作用可能部分解释为AMPK调节骨骼肌自噬的其他作用。对于清除受损和/或功能失调的细胞器至关重要的细胞过程。从这些数据中可以得出两个主要结论：（1）fukutin缺失产生内在的肌肉代谢缺陷，这可能导致营养不良的疾病病理，和（2）AICAR治疗加速损伤后肌肉收缩功能的恢复，提示AMPK信号作为治疗策略的可能靶标。
肌营养不良蛋白-糖蛋白复合物（DGC）的破坏显然是各种形式的肌营养不良和营养不良症的主要基础。但是DGC破坏的细胞后果仍在研究中。线粒体异常正在成为营养不良疾病病理的明显后果和贡献者。在这里，我们证明了fukutin基因的肌肉特异性缺失（Myf5/fktn-KO小鼠（FktnKO）），继发性营养不良的模型，结果与健康同窝对照（LM）相比，肌肉力量降低了30％（P<0.001），线粒体呼吸功能降低了16％（P=0.002）。我们还观察到过氧化物酶体增殖物激活受体-γ共激活因子1α（PGC-1α）基因的表达降低了80％（P=0.004），线粒体生物发生的主要转录因子，在FktnKO小鼠中，可能导致线粒体缺陷。PGC-1α通过AMP激活的蛋白激酶（AMPK）的磷酸化进行翻译后调节。使用AMPK激动剂5-氨基咪唑-4-甲酰胺核糖核苷酸（AICAR）治疗未能挽救FktnKO小鼠的线粒体缺陷（P=0.458），但确实对恢复肌肉收缩性有益（〜30％以上）与盐水治疗相比，LM和FktnKO小鼠受伤后的收缩力（P=0.006）。通过AICAR刺激AMPK对肌肉收缩功能的有益作用可能部分解释为AMPK调节骨骼肌自噬的其他作用。对于清除受损和/或功能失调的细胞器至关重要的细胞过程。从这些数据中可以得出两个主要结论：（1）fukutin缺失产生内在的肌肉代谢缺陷，这可能导致营养不良的疾病病理，和（2）AICAR治疗加速损伤后肌肉收缩功能的恢复，提示AMPK信号作为治疗策略的可能靶标。
