# Enhancement of Aged Skeletal Muscle Contractility and Muscle Quality by Administration of Trimetazidine

> **NIH NIH R03** · UNIVERSITY OF SOUTH FLORIDA · 2020 · $74,750

## Abstract

ABSTRACT
Age-related muscle weakness is a significant problem that carries enormous healthcare costs resulting from its
contributions to disability, impaired mobility & independence and even overall mortality. Mounting evidence
indicates that this weakness results more from a loss of muscle quality (strength per unit muscle mass) than
muscle atrophy, indicating a need to pursue interventional strategies other than increasing muscle mass.
Recent, limited, data suggest that trimetazidine (TMZ) , a non-hemodynamic anti-angina drug, may enhance
muscle function in aged rats, without affecting muscle size. However those data include only behavioral
performance tests, with no direct measures of muscle strength; neither do they discriminate among muscular
or neural mechanisms. This proposed work addresses these gaps by providing definitive measures of muscle
contractile function following treatment with TMZ. Our laboratory has published findings that aged muscles
that exhibit impaired muscle quality, also show impaired Ca2+ release by the sarcoplasmic reticulum (SR) – the
intramuscular storehouse of calcium that is mobilized to produce muscle contraction. Further evidence
indicates that TMZ may act to address several mechanism linked to muscle quality and SR function, including:
reduced autophagy, increased oxidative injury and altered lipid metabolism. Thus, there is a theoretical basis
for TMZ to improve aged muscle function, supported by our preliminary data, by increasing aged muscle
contractility, reducing SR lipid peroxidation and enhancing SR Ca2+ release. Combined with our published
data, these findings provide the basis for this small, self-contained pre-clinical study. Our central hypothesis is
that TMZ treatment will enhance force production by improving SR function in aged muscles. We further
predict that TMZ will stimulate aged muscle autophagy, and reduce SR lipid peroxidation. Accordingly, our
proposed study will combine a range of methodologies to assess the effects of TMZ on muscle function and
morphology. We will test contractile responses to both neural (in situ) and direct (ex vivo) electrical stimulation
in an established rat model of aging. This combination will allow us to determine the relative contribution of
neuromuscular vs. intramuscular mechanisms changes in muscle force. We will also directly assess SR
function (e.g., Ca2+ release) lipid peroxidation and morphology (via electron microscopy). We will also assess
effect of TMZ on basal autophagic flux in skeletal muscle. While we predict that TMZ will improve aged muscle
function by improving SR function, our approach will allow us to probe alternative mechanisms (e.g.,
neuromuscular junction stability, muscle hypertrophy), should the results warrant. If our hypotheses are
confirmed, short-term future work will be directed at more thoroughly investigating mechanisms of action (e.g.,
lipidomic analysis of the SR) as well as dose-response characteristics will be pursued. The lon...

## Key facts

- **NIH application ID:** 9870328
- **Project number:** 1R03AG065828-01
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** David W Russ
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $74,750
- **Award type:** 1
- **Project period:** 2020-02-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9870328

## Citation

> US National Institutes of Health, RePORTER application 9870328, Enhancement of Aged Skeletal Muscle Contractility and Muscle Quality by Administration of Trimetazidine (1R03AG065828-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9870328. Licensed CC0.

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