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 VO2peak) 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.

Molecular Choreography of Acute Exercise

“…C6:1, C8:1) accumulated to a lesser extent and returned to baseline more slowly (30 min to 1 hour) ( Figure 2e ). The increased abundance of circulating medium chain acylcarnitines reflects partial FAO in skeletal muscle (Lehmann et al, 2010; Zhang et al, 2017). The level of circulating free carnitine demonstrated an inverse trajectory (cluster 3) since it is used to form acylcarnitines from free fatty acids.…”

Blood cytokine patterns suggest a modest inflammation phenotype in subjects with long‐chain fatty acid oxidation disorders

“…; Zhang et al. ). Cardiac ischemia is another condition in which tissue LCACs and other lipids accumulate markedly, especially in heart regions with ischemic damage (Idell‐Wenger et al.…”

Skeletal muscle interstitial fluid metabolomics at rest and associated with an exercise bout: application in rats and humans

“…During acute exercise, fuel "crossover" occurs as muscle work increases in terms of maximal or peak O 2 uptake, the relative carbohydrate contribution to ATP needs (percentage of energy requirements met by carbohydrates) increases, and the relative role of fatty acids wanes (6). An acute submaximal exercise bout led to significant increases (from rest) in plasma indexes of incomplete fatty acid (medium-chain acylcarnitines) oxidation (FAO) (46), in line with other reports (16,24). Other studies have examined broader exercise-associated metabolite patterns through application of metabolomics in blood (8,9,16,25,29,(31)(32)(33)(34)(35)(36) or in a limited number of muscle biopsy studies (7,12).…”