Cytosolic adaptation to mitochondria-induced proteostatic stress causes progressive muscle wasting

Xiaowen Wang; Frank A Middleton; Rabi Tawil; Xin Jie Chen

doi:10.1016/j.isci.2021.103715

Cytosolic adaptation to mitochondria-induced proteostatic stress causes progressive muscle wasting

iScience. 2021 Dec 31;25(1):103715. doi: 10.1016/j.isci.2021.103715. eCollection 2022 Jan 21.

Authors

Xiaowen Wang¹, Frank A Middleton², Rabi Tawil³, Xin Jie Chen^{1

2}

Affiliations

¹ Department of Biochemistry and Molecular Biology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA.
² Department of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA.
³ Department of Neurology, University of Rochester, Rochester, NY 14642, USA.

Abstract

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 Ant1-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 Ant1 overexpression, including facioscapulohumeral dystrophy.

Keywords: Biological sciences; Cell biology; Cellular physiology; Functional aspects of cell biology.

Abstract

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