Plasma proteomic analysis of intermuscular fat links muscle integrity with processing speed in older adults

INTRODUCTION

More intermuscular fat (IMF) has been associated with lower cognitive performance through mechanisms that are not fully elucidated.

METHODS

The associations of 7628 plasma proteins with IMF were assessed in the Baltimore Longitudinal Study on Aging ( n  = 941, mean age = 66.7 ± 15.2) and validated in the Coronary Artery Risk Development in Young Adults Study ( n  = 2451, mean age = 50.2 ± 3.6). Processing speed was assessed by Digit Symbol Substitution Test (DSST). Associations between the main exposures, outcome, and mediators were evaluated using linear regression, and mediating effects were assessed by causal mediation analysis.

RESULTS

There were 722 plasma proteins associated with IMF in both the discovery and replication cohorts (false discovery rate [FDR] adjusted p  ≤ 0.05). Of these, 26 mediated the relationship between IMF and DSST, with effects ranging from 2.8% to 20.9% ( p  ≤ 0.05). These proteins represented synaptic function and organization, and growth factor binding (FDR adjusted p  ≤ 0.05).

DISCUSSION

Reducing IMF may improve processing speed through effects on growth factor and synaptic activity.

Highlights

• Higher intermuscular fat is associated with lower processing speed, consistently across populations that represent different demographic characteristics.

• There is a robust plasma proteomic profile of intermuscular fat that is assessed in the abdominal and thigh skeletal muscle.

• The proteins associated with intermuscular fat reflect signals that are reflective of synaptic function and organization, as well as other molecular pathways such as growth factor binding.

• Circulating proteins partially explain the association between higher intermuscular fat and lower processing speed, suggesting that higher intermuscular fat effects processing speed through pathways including synaptic functions and growth factor binding.