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Updated: Aug 6, 2026
08:12
Measurement of Mitochondrial Respiration in Human and Mouse Skeletal Muscle Fibers by High-Resolution Respirometry
Published on: October 4, 2024
Muscle Mitochondrial Oxidative Capacity and Cognitive Decline Over up to a Decade: Sex Differences
Qu Tian1, Anjay Ambegaonkar1, Luigi Ferrucci1
1Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, Baltimore, Maryland, USA.
Aging Cell
|July 21, 2026
Summary
Higher muscle mitochondrial function (kPCr) is linked to better cognition in older adults. This association predicts slower cognitive decline, particularly in men, with distinct underlying mechanisms observed between sexes.
Area of Science:
- Gerontology
- Neuroscience
- Metabolism
Background:
- Higher skeletal muscle oxidative capacity correlates with improved cognitive function and brain structure.
- Mitochondrial health is increasingly recognized as crucial for brain health, yet sex-specific relationships with cognition remain underexplored.
- Understanding these sex differences is vital for targeted interventions to maintain cognitive function in aging populations.
Purpose of the Study:
- To investigate the relationship between skeletal muscle mitochondrial oxidative capacity and cognitive function in older adults.
- To examine potential sex differences in the association between muscle oxidative capacity and cognitive performance, both cross-sectionally and longitudinally.
- To explore the underlying biological mechanisms, including blood-based clinical markers, that mediate these relationships.
Main Methods:
- Utilized phosphorus-31 magnetic resonance spectroscopy (MRS) to assess muscle oxidative capacity via the recovery rate of phosphocreatine (kPCr) post-exercise.
- Analyzed prospective cognitive data over up to 12 years in 506 older participants (mean age 74.4 years, 58% women) using linear mixed-effects models.
- Computed cognitive composite scores and tested mediation effects of various blood-based clinical markers.
Main Results:
- Cross-sectionally, higher kPCr was associated with higher cognitive scores in both men and women, with no significant sex interaction.
- Longitudinally, a significant interaction between kPCr and sex (p=0.042) indicated that higher kPCr was associated with slower cognitive decline, particularly in men, especially for executive function and processing speed.
- Mediation analyses revealed distinct pathways: in men, fasting glucose and hemoglobin A1C mediated the kPCr-cognition link; in women, ESR, hemoglobin, and hematocrit played a mediating role.
Conclusions:
- Skeletal muscle mitochondria are linked to cognitive function and predict cognitive decline, with a more pronounced effect observed in men.
- The underlying biological mechanisms mediating the muscle-mitochondria-cognition axis appear to differ significantly between sexes.
- Metabolic pathways may drive these associations in men, while hematologic-inflammatory pathways might be more relevant in women, warranting further omics investigation.
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