Wang Xiaowen, Middleton Frank A, Tawil Rabi, Chen Xin Jie
Department of Biochemistry and Molecular Biology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA.
Department of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA.
iScience. 2021 Dec 31;25(1):103715. doi: 10.1016/j.isci.2021.103715. eCollection 2022 Jan 21.
Mitochondrial dysfunction causes muscle wasting in many diseases and probably also during aging. The underlying mechanism is poorly understood. We generated transgenic mice with unbalanced mitochondrial protein loading and import, by moderately overexpressing the nuclear-encoded adenine nucleotide translocase, Ant1. We found that these mice progressively lose skeletal muscle. Ant1-overloading reduces mitochondrial respiration. Interestingly, it also induces small heat shock proteins and aggresome-like structures in the cytosol, suggesting increased proteostatic burden due to accumulation of unimported mitochondrial preproteins. The transcriptome of -transgenic muscles is drastically remodeled to counteract proteostatic stress, by repressing protein synthesis and promoting proteasomal function, autophagy, and lysosomal amplification. These proteostatic adaptations collectively reduce protein content thereby reducing myofiber size and muscle mass. Thus, muscle wasting can occur as a trade-off of adaptation to mitochondria-induced proteostatic stress. This finding could have implications for understanding the mechanism of muscle wasting, especially in diseases associated with overexpression, including facioscapulohumeral dystrophy.
线粒体功能障碍在许多疾病中都会导致肌肉萎缩，在衰老过程中可能也是如此。其潜在机制尚不清楚。我们通过适度过表达核编码的腺嘌呤核苷酸转位酶Ant1，培育出了线粒体蛋白负载和导入失衡的转基因小鼠。我们发现这些小鼠的骨骼肌逐渐减少。Ant1过载会降低线粒体呼吸。有趣的是，它还会在细胞质中诱导小热休克蛋白和聚集体样结构，这表明由于未导入的线粒体前体蛋白的积累，蛋白稳态负担增加。转基因肌肉的转录组会发生剧烈重塑，通过抑制蛋白质合成、促进蛋白酶体功能、自噬和溶酶体扩增来对抗蛋白稳态应激。这些蛋白稳态适应共同降低了蛋白质含量，从而减小了肌纤维大小和肌肉质量。因此，肌肉萎缩可能是适应线粒体诱导的蛋白稳态应激的一种权衡。这一发现可能有助于理解肌肉萎缩的机制，尤其是在与过表达相关的疾病中，包括面肩肱型肌营养不良症。
