# Metabolic remodeling of skeletal muscle in mitochondrial myopathies

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $533,742

## Abstract

Project Summary
Mitochondrial diseases are heterogeneous genetic disorders caused by the impairment of the
oxidative phosphorylation (OXPHOS) system, affecting tissues that are heavily energy
dependent, and often manifesting with neuromuscular symptoms accompanied by a variety of
additional clinical features. Although the energetic defects arising from genetic errors in
mitochondrial and nuclear DNA are often known, many aspects of mitochondrial disease
pathogenesis are yet to be elucidated. As a consequence, because of the lack of defined
metabolic targets, no proven effective treatments or cures are available. Our recently published
studies indicate that a dramatic metabolic remodeling occurs in the skeletal muscle of a mouse
model of mitochondrial myopathy. We found that a starvation-like response promotes muscle
protein breakdown and amino acid catabolism to support a compensatory energy-generating
oxidative flux. In this flux, glutamate is oxidized through the TCA cycle and allows for OXPHOS-
independent substrate-level ADP phosphorylation. However, this compensatory process results
in muscle wasting and lipids accumulation. We hypothesize that in addition to ATP synthesis
impairment, OXPHOS-defective tissues must face a number of dysmetabolic problems caused
by altered pathways of the intermediary metabolism. Importantly, in preliminary studies leading
to this application, we have discovered that skeletal muscle from human patients with
mitochondrial myopathy show similar compensatory metabolic responses. Our findings suggest
that this metabolic shift towards preferred utilization of amino acids over lipids for energetic
purposes underlies maladaptive effects, contributing to disease pathogenesis.
In aim 1 of this application, we will investigate in depth the mechanisms and roles of the
metabolic rewiring in OXPHOS-defective muscle of a mouse model of mitochondrial myopathy.
In aim 2 we will investigate the muscle metabolic remodeling in human mitochondrial myopathy.
In aim 3 we will test metabolic supplementation therapy in the mitochondrial myopathy mouse.
At the conclusion of this study we will have improved our knowledge on the pathogenic
mechanisms of mitochondrial diseases, established a functional biomarker panel for human
mitochondrial myopathy, and assessed if metabolic supplementation can improve the myopathic
phenotype.

## Key facts

- **NIH application ID:** 10134249
- **Project number:** 5R01AR076029-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Qiuying Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $533,742
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134249

## Citation

> US National Institutes of Health, RePORTER application 10134249, Metabolic remodeling of skeletal muscle in mitochondrial myopathies (5R01AR076029-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10134249. Licensed CC0.

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