Muscle Mitochondrial Oxidative Capacity and Cognitive Decline Over up to a Decade: Sex Differences

Abstract

Higher skeletal muscle oxidative capacity is associated with higher cognitive function and preserved brain structure. The relationship between mitochondria and brain health suggests sex differences, but whether the relationship with cognition shows sex differences and underlying mechanisms is unknown. We analyzed the relationships between mitochondrial oxidative capacity and up to 12-year prospective cognitive data in 506 older participants (mean age = 74.4 years, 58% Women) and examined sex differences, using linear mixed-effects models adjusted for demographics. Cognitive composite scores were computed using multiple cognitive measures. Muscle oxidative capacity was assessed as the post-exercise recovery rate of phosphocreatine (kPCr) via phosphorus-31 MR spectroscopy. We tested mediation effects of blood-based clinical markers. Cross-sectionally, higher kPCr was associated with higher cognitive scores (p < 0.001 overall, p = 0.001 men, p = 0.029 women), and there was no significant kPCr-by-sex interaction (p = 0.308). Longitudinally, there was a significant kPCr-by-sex interaction (p = 0.042). The association of higher kPCr with slower cognitive decline was prominent in men (p = 0.077), particularly executive function (p = 0.010) and processing speed (p = 0.049). In men, fasting glucose and hemoglobin A1C mediated both cross-sectional and longitudinal associations between kPCr and cognition (all p < 0.05, 23.1% by glucose). Total protein and globulin also mediated the cross-sectional association in men to a lesser extent (9.5%–9.9%). In women, ESR, hemoglobin, and hematocrit mediated the cross-sectional association (all p < 0.05, 22.7% by hematocrit). Muscle mitochondria are linked to cognition and predict cognitive decline primarily in men. Underlying mechanisms appear to differ by sex, likely through a metabolic-drive pathway in men and a hematologic-inflammatory pathway in women. Omics studies are warranted to elucidate the sex-specific biological processes.