In vivo mitochondrial ATP production is improved in older adult skeletal muscle after a single dose of elamipretide in a randomized trial
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Abstract
Background: Loss of mitochondrial function contributes to fatigue, exercise intolerance and muscle weakness, and is a key factor in the disability that develops with age and a wide variety of chronic disorders. Here, we describe the impact of a first-in-class cardiolipin-binding compound that is targeted to mitochondria and improves oxidative phosphorylation capacity (Elamipretide, ELAM) in a randomized, double-blind, placebo-controlled clinical trial. Methods: Non-invasive magnetic resonance and optical spectroscopy provided measures of mitochondrial capacity (ATP max ) with exercise and mitochondrial coupling (ATP supply per O 2 uptake; P/O) at rest. The first dorsal interosseous (FDI) muscle was studied in 39 healthy older adult subjects (60 to 85 yrs of age; 46% female) who were enrolled based on the presence of poorly functioning mitochondria. We measured volitional fatigue resistance by force-time integral over repetitive muscle contractions. Results: A single ELAM dose elevated mitochondrial energetic capacity in vivo relative to placebo (ΔATP max ; P = 0.055, %ΔATP max ; P = 0.045) immediately after a 2-hour infusion. No difference was found on day 7 after treatment, which is consistent with the half-life of ELAM in human blood. No significant changes were found in resting muscle mitochondrial coupling. Despite the increase in ATP max there was no significant effect of treatment on fatigue resistance in the FDI. Conclusions: These results highlight that ELAM rapidly and reversibly elevates mitochondrial capacity after a single dose. This response represents the first demonstration of a pharmacological intervention that can reverse mitochondrial dysfunction in vivo immediately after treatment in aging human muscle.
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A clinical study published in 2021 found that elamipretide reverses mitochondrial dysfunction in ageing human muscle.
“one clinical study published in 2021 showed that elamipretide reverses mitochondrial dysfunction in ageing human muscle”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [293]
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- Authors
- Roshanravan, B., Liu, S. Z., Ali, A. S., Shankland, E. G., Goss, C., Amory, J. K., Robertson, H. T., Marcinek, D. J., & Conley, K. E.
- Affiliations
- University of California Davis Medical Center (US)
- University of Washington (US)
- Corresponding author
- Marcinek, David J.
- ORCID
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2021-07-15
- Volume
- 16
- Issue
- 7
- Pages
- e0253849
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC8282018
- OpenAlex
- W3180296007
- Cited by
- 38
- References
- 49
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 5 · 2023: 12 · 2022: 7
- FWCI
- 1.88
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- medRxiv (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Stealth BioTherapeutics
- National Institutes of Health (P01AG001751, 5T32AG5738, UL1TR000423, 1S10OD016201, K23DK099442)
- UW Department of Radiology
- UW Office of the Provost
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- elamipretide, mitochondrial dysfunction, skeletal muscle aging, ATP production, oxidative phosphorylation, mitochondrial coupling, fatigue resistance, first dorsal interosseous muscle, older adults
- MeSH terms
- Adenosine Triphosphate, Aged, Aged, 80 and over, Double-Blind Method, Female, Humans, Male, Middle Aged, Mitochondria, Muscle, Muscle Contraction, Oligopeptides, Exercise, Muscle, Skeletal, Muscle Fatigue
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