# Mechanism of Mitochondria-induced Progressive Muscle Wasting

> **NIH NIH R01** · UPSTATE MEDICAL UNIVERSITY · 2021 · $396,696

## Abstract

Muscle wasting (or atrophy) is defined by reduced myofiber size, number and strength. It occurs in aging,
muscle disuse, denervation, cancer, AIDS, diabetes and cardiac failure, which increases frailty, morbidity
and mortality. Under physiological conditions, myofiber size is maintained by a balance between protein
synthesis and degradation. How proteostasis is unbalanced under various atrophying conditions is poorly
understood. Mitochondrial dysfunction has been proposed to contribute to progressive muscle atrophy. Most
studies have been focused on the role of mitochondria in energy production, oxidative stress and apoptosis.
However, recent studies showed that considerable levels of bioenergetic deficiency and oxidative stress are
not sufficient to cause myofiber shrinkage and progressive muscle wasting. If mitochondrial stress causes
muscle wasting, it would have to involve a novel mechanism. We recently generated a transgenic mouse
line that moderately overexpresses Ant1, the muscle/heart isoform of adenine nucleotide translocase
involved in ATP/ADP exchange across the inner membrane of mitochondria (IMM), to model one of the
most common muscle diseases known as Facioscapulohumeral Muscular Dystrophy (FSHD). We found that
the ANT1-transgenic mice have reduced myofiber size and progressively lose muscle mass. Our preliminary
studies support the idea that, in addition to moderate bioenergetic defect, ANT1-overexpression causes
proteostatic stress in the cytosol. We hypothesize that Ant1 overloading may disturb protein import and
cause mitochondrial Precursor Overaccumulation Stress (mPOS), a novel mitochondria-induced stress
characterized by the overaccumulation of unimported proteins in the cytosol. We also propose that
proteostatic adaptation to mPOS may chronically reduce protein synthesis and increase protein
degradation, which ultimately leads to muscle wasting. In this application, we will test these hypotheses by
proposing the following specific aims. (1) We will test whether moderate ANT1 overexpression is sufficient
to induce proteostatic stress in the cytosol. (2) We will identify cytosolic pathways that are important for the
triage of unimported mitochondrial proteins. (3) We will test the hypothesis that Ant1-induced muscle
atrophy results from reduced protein synthesis and/or increased proteasomal and autophagy activities,
triggered as stress responses to mPOS. Success of the project may lead to the discovery of a novel
mechanism by which mitochondria affect muscle mass homeostasis. The results could have direct
implications for the understanding of several diseases that involve ANT1 overexpression, including FSHD,
dilated cardiomyopathy and Rett syndrome. Finally, the validation of the mPOS model in mice could have
broad implications for the understanding of other mitochondrial disorders that affect protein import.

## Key facts

- **NIH application ID:** 10062793
- **Project number:** 5R01AG061204-03
- **Recipient organization:** UPSTATE MEDICAL UNIVERSITY
- **Principal Investigator:** Xin Jie Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $396,696
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10062793

## Citation

> US National Institutes of Health, RePORTER application 10062793, Mechanism of Mitochondria-induced Progressive Muscle Wasting (5R01AG061204-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10062793. Licensed CC0.

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