# Mitochondrial Permeability Transitionin Aging Muscle

> **NIH NIH R56** · UNIVERSITY OF FLORIDA · 2021 · $312,625

## Abstract

Project Summary/Abstract
Mitochondrial permeability transition (MPT) involves the formation of a non-specific pore across the mitochondrial
inner membrane that allows the passage of pro-apoptotic proteins and induces a large burst in reactive oxygen
species (ROS). Whilst the pathological role of MPT in ischemia-reperfusion injury, cardiac aging, muscular
dystrophy and neurodegeneration is well-established, the role of MPT in aging skeletal muscle has not been
resolved. Our preliminary data in human and rodent muscle cell cultures identify MPT as a novel mechanism of
muscle atrophy that can be blocked by interfering with proteins that regulate MPT, knocking down caspase 3, or
by quenching mitochondrial ROS. Furthermore, we show that mitochondria have a lower threshold for inducing
MPT in aging muscle, that there is an increased occurrence of MPT in aging human skeletal muscle, and that it
only occurs in muscles that atrophy with aging, Finally, we also show in aged muscles that muscle fibers with
mitochondria undergoing MPT are severely atrophied relative to normal muscle fibers and that they exhibit
features suggesting they are denervated. On this basis, the first goal of this project is to address the fundamental
mechanisms linking MPT to muscle atrophy using cell culture models. Secondly, using rat models we will
manipulate the Ca2+ threshold for MPT to test the necessity and sufficiency of MPT for generating aging muscle
phenotypes. Finally, we will leverage the powerful clinical dataset, deep muscle phenotyping, and availability of
muscle histology blocks from the Study of Muscle Mobility and Aging (SOMMA) that will study 875 elderly men
and women (³70 y), to establish the translational relevance of MPT for important clinical outcomes in elderly
humans. By doing so, our studies will lay the foundation necessary to judge the merits of developing novel
therapeutic approaches to prevent sensitization of mitochondria to MPT as a means of preserving muscle mass
and mobility in advanced age.

## Key facts

- **NIH application ID:** 10426409
- **Project number:** 1R56AG066758-01A1
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Russell T Hepple
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $312,625
- **Award type:** 1
- **Project period:** 2021-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10426409

## Citation

> US National Institutes of Health, RePORTER application 10426409, Mitochondrial Permeability Transitionin Aging Muscle (1R56AG066758-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10426409. Licensed CC0.

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