Acylcarnitines as markers of exercise-associated fuel partitioning, xenometabolism, and potential signals to muscle afferent neurons

Abstract

With insulin-resistance or type 2 diabetes mellitus, mismatches between mitochondrial fatty acid fuel delivery and oxidative phosphorylation/tricarboxylic acid cycle activity may contribute to inordinate accumulation of short- or medium-chain acylcarnitine fatty acid derivatives (markers of incomplete long-chain fatty acid oxidation [FAO]). We reasoned that incomplete FAO in muscle would be ameliorated concurrent with improved insulin sensitivity and fitness following a ~14 wk training and weight loss intervention in obese, sedentary, insulin-resistant women. Contrary to this hypothesis, overnight-fasted and exercise-induced plasma C4-C14 acylcarnitines did not differ between pre-intervention and post-intervention phases. These metabolites all increased robustly with exercise (~45% of pre-intervention VO _2peak) and decreased during a 20 min cool-down. This supports the idea that, regardless of insulin sensitivity and fitness, intramitochondrial muscle β-oxidation and attendant incomplete FAO are closely tethered to absolute ATP turnover rate. Acute exercise also led to branched-chain amino acid (BCAA) acylcarnitine derivative patterns suggestive of rapid diminution of BCAA flux through mitochondrial branched-chain ketoacid dehydrogenase complex. We confirmed our prior novel observation that weight loss/fitness intervention alters plasma xenometabolites (i.e., cis-3,4-methylene-heptanoylcarnitine and γ-butyrobetaine [a co-metabolite possibly derived in part from gut bacteria]), suggesting that host metabolic health regulated gut microbe metabolism. Finally, we considered if acylcarnitine metabolites signal to muscle-innervating afferents: palmitoylcarnitine at concentrations as low as 1–10 μM activated a sub-set (~2.5–5%) of these neurons ex vivo. This supports the hypothesis that in addition to tracking exercise-associated shifts in fuel metabolism, muscle acylcarnitines act as exertion signals to short-loop somatosensory-motor circuits or to the brain.