Divergent Skeletal Muscle Metabolomic Signatures of Different Exercise Training Modes Independently Predict Cardiometabolic Risk Factors

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We investigated the link between enhancement of insulin sensitivity (SI) (by hyperinsulinemic-euglycemic clamp) and muscle metabolites following 12-weeks of aerobic (high-intensity interval training, HIIT), resistance (RT), or combined (CT) exercise training in 52 lean healthy people. Muscle RNA-sequencing revealed a significant association between SI following both HIIT and RT and the branched chain amino acid (BCAA) metabolic pathway. Concurrent to increased expression and activity of branched chain ketoacid dehydrogenase enzyme, many muscle amino metabolites including BCAAs, glutamate, phenylalanine, aspartate, asparagine, methionine, and GABA increased by HIIT, supporting substantial impact of HIIT on amino acid metabolism. Short-chain C3 and C5 acylcarnitines were reduced in muscle by all three training modes, but unlike RT, both HIIT and CT increased TCA metabolites and cardiolipins, supporting greater mitochondrial activity by aerobic training. Conversely, RT and CT increased more plasma membrane phospholipids than HIIT, suggesting a resistance exercise effect on cellular membrane protection against environmental damage. Sex and age contributed modestly to the exercise-induced changes in metabolites and their association to cardiometabolic parameters. Integrated transcriptomic and metabolomic analyses suggest various clusters of genes and metabolites are involved in distinct effects of HIIT, RT, and CT. These distinct metabolic signatures of different exercise modes independently link each type of exercise training to improved SI and cardiometabolic risk. ARTICLE HIGHLIGHTS: · We aimed to understand the link between skeletal muscle metabolites and cardiometabolic health after exercise training. · Although aerobic, resistance, and combined exercise training each enhance muscle insulin sensitivity as well as other cardiometabolic parameters, they disparately alter amino and citric acid metabolites as well as lipidome, linking these metabolomic changes independently to improvement of cardiometabolic risks by each exercise training mode. · These findings reveal an important layer of the unique exercise mode-dependent changes in muscle metabolism which may eventually lead to more informed exercise prescription for improving SI.

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