The Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD, USA.
Cellular and Molecular Medicine Graduate Program, Johns Hopkins School of Medicine, Baltimore, MD, USA.
FASEB J. 2021 Feb;35(2):e21276. doi: 10.1096/fj.202002106RR.
Mitochondrial derangement is an important contributor to the pathophysiology of muscular dystrophies and may be among the earliest cellular deficits. We have previously shown that disruption of Mss51, a mammalian skeletal muscle protein that localizes to the mitochondria, results in enhanced muscle oxygen consumption rate, increased endurance capacity, and improved limb muscle strength in mice with wildtype background. Here, we investigate whether Mss51 deletion in the mdx murine model of Duchenne muscular dystrophy (mdx-Mss51 KO) counteracts the muscle pathology and mitochondrial irregularities observed in mdx mice. We found that mdx-Mss51 KO mice had increased myofiber oxygen consumption rates and an amelioration of muscle histopathology compared to mdx counterparts. This corresponded with greater treadmill endurance and less percent fatigue in muscle physiology, but no improvement in forelimb grip strength or limb muscle force production. These findings suggest that although Mss51 deletion ameliorates the skeletal muscle mitochondrial respiration defects in mdx and improves fatigue resistance in vivo, the lack of improvement in force production suggests that this target alone may be insufficient for a therapeutic effect.
线粒体紊乱是肌肉疾病病理生理学的一个重要贡献者，并且可能是最早的细胞缺陷之一。我们之前已经表明，破坏哺乳动物骨骼肌蛋白 Mss51（它定位于线粒体）会导致野生型背景下的小鼠的肌肉耗氧量增加、耐力能力增强以及肢体肌肉力量提高。在这里，我们研究了 Duchenne 肌肉营养不良症（mdx-Mss51 KO）的 mdx 小鼠模型中的 Mss51 缺失是否可以抵消 mdx 小鼠中观察到的肌肉病理学和线粒体不规则性。我们发现 mdx-Mss51 KO 小鼠的肌纤维耗氧量增加，并且与 mdx 对照相比，肌肉组织病理学得到改善。这与跑步机耐力的提高和肌肉生理学中疲劳百分比的降低相对应，但在前肢握力或肢体肌肉力量产生方面没有改善。这些发现表明，尽管 Mss51 缺失可改善 mdx 的骨骼肌线粒体呼吸缺陷并提高体内抗疲劳能力，但力量产生方面没有改善表明仅针对该靶点可能不足以产生治疗效果。
