# Role of Skeletal Muscle Mitochondrial Supercomplexes in Exercise Intolerance

> **NIH VA I01** · PROVIDENCE VA  MEDICAL CENTER · 2022 · —

## Abstract

ABSTRACT
Pulmonary hypertension is associated with poor quality of life, impaired functional tolerance and limitation of
physical activity. Despite optimal available therapy for PH, patients report fatigue, decreased functional
capacity, and worsening quality of life. Exercise intolerance (i.e. reduced VO2 max) is associated with reduced
skeletal muscle (SkM) mitochondrial function and cellular respiration. Recent studies have demonstrated that
changes in organization of electron transport chain complexes can significantly alter mitochondrial respiration
and energy production. Binding of individual electron transport chain complexes into large molecular weight
supercomplexes (SC) increases respiration efficiency, reduces damaging ROS, and improves ATP production.
SC can consist of complex I and multiple units of complex III and IV in direct association to allow direct electron
transfer. In preliminary studies, we have found that SkM in rats with PH have greatly reduced I/III/IV
supercomplex assembly and this is associated with reduced VO2 max determined by maximal treadmill
exercise capacity. Our central hypothesis is that reduction in mitochondrial SC in SkM contributes to exercise
intolerance in PH, and that increasing SC can alleviate PH-induced SkM dysfunction. We will test this
hypothesis using a well-established rat model of pulmonary hypertension that recapitulates the
pathophysiological aspects as well as exercise intolerance observed in patients with PH. In Aim 1, we will
evaluate PH-induced changes in SkM mitochondrial SC formation and associated changes in respiratory
function, mitochondrial content, and cristae architecture in a preclinical PH model and PH patients. In addition
we will verify these changes are indeed present in human SkM samples from PH patients. In Aim 2, we will
determine molecular mechanisms underlying altered mitochondrial function and SC assembly in isolated SkM
fibers and differentiated primary SkM myotubes from control and PH animals Finally in Aim 3, we will
determine if increasing mitochondrial supercomplex formation in SkM by exercise or drug therapy results in
improved functional capacity (i.e. VO2 max). These will be the first studies to evaluate the role of mitochondrial
SC in exercise intolerance associated with chronic medical condition such as PH, and the first studies to
directly target SC assembly to alleviate SkM dysfunction.

## Key facts

- **NIH application ID:** 10409709
- **Project number:** 5I01CX001892-04
- **Recipient organization:** PROVIDENCE VA  MEDICAL CENTER
- **Principal Investigator:** Gaurav Choudhary
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10409709

## Citation

> US National Institutes of Health, RePORTER application 10409709, Role of Skeletal Muscle Mitochondrial Supercomplexes in Exercise Intolerance (5I01CX001892-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10409709. Licensed CC0.

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