The mediation roles of intermuscular fat and inflammation in muscle mitochondrial associations with cognition and mobility

Background: Mitochondrial dysfunction may contribute to brain and muscle health through inflammation or fat infiltration in the muscle, both of which are associated with cognitive function and mobility. We aimed to examine the association between skeletal muscle mitochondrial function and cognitive and mobility outcomes and tested the mediation effect of inflammation or fat infiltration.Methods: We analysed data from 596 Baltimore Longitudinal Study of Aging participants who had concurrent data on skeletal muscle oxidative capacity and cognitive and mobility measures of interest (mean age: 66.1, 55% women, 24% Black). Skeletal muscle oxidative capacity was assessed as post-exercise recovery rate (kPCr) via P31 MR spectroscopy. Fat infiltration was measured as intermuscular fat (IMF) via CT scan and was available for 541 participants. Inflammation markers [IL-6, C-reactive protein (CRP), total white blood cell (WBC), neutrophil count, erythrocyte sedimentation rate (ESR), or albumin] were available in 594 participants. We examined the association of kPCr and cognitive and mobility measures using linear regression and tested the mediation effect of IMF or inflammation using the mediation package in R. Models were adjusted for demographics and PCr depletion.Results: kPCr and IMF were both significantly associated with specific cognitive domains (DSST, TMA-A, and pegboard dominant hand performance) and mobility (usual gait speed, HABCPPB, 400 m walk time) (all P < 0.05). IMF significantly mediated the relationship between kPCr and these cognitive and mobility measures (all P < 0.05, proportion mediated 13.1% to 27%). Total WBC, neutrophil count, and ESR, but not IL-6 or CRP, also mediated at least one of the cognitive and mobility outcomes (all P < 0.05, proportion mediated 9.4% to 15.3%).Conclusions: Skeletal muscle mitochondrial function is associated with cognitive performance involving psychomotor speed. Muscle fat infiltration and specific inflammation markers mediate the relationship between muscle mitochondrial function and cognitive and mobility outcomes. Future studies are needed to confirm these associations longitudinally and to understand their mechanistic underpinnings.