J Physiol. 2023 Feb 22.
J Matthew Hinkley,
GongXin Yu,
Robert A Standley,
Giovanna Distefano,
Vladimir Tolstikov,
Niven R Narain,
Bennett P Greenwood,
Shraddha Karmacharya,
Michael A Kiebish,
Elvis Alvarez Carnero,
Fanchao Yi,
Rick B Vega,
Bret H Goodpaster,
Stephen J Gardell,
Paul M Coen.
Exercise-induced perturbation of skeletal muscle metabolites is a likely mediator of long-term health benefits in older adults. While specific metabolites have been identified to be impacted by age, physical activity, and exercise, the depth of coverage of the muscle metabolome is still limited. Here, we investigated resting and exercise-induced metabolite distribution in muscle from well-phenotyped older adults that were active or sedentary, and a group of active young adults. Percutaneous biopsies of the vastus lateralis were obtained before, immediately after, and 3-hours following a bout of endurance cycling. Metabolite profile in muscle biopsies was determined by tandem mass spectrometry. Mitochondrial energetics in permeabilized fiber bundles was assessed by high resolution respirometry and fiber type proportion was assessed by immunohistology. We found that metabolites of the kynurenine/tryptophan pathway were impacted by age and activity. Specifically, kynurenine was elevated in muscle from older adults, while downstream metabolites of kynurenine (kynurenic acid and nicotinamide adenine dinucleotide (NAD+ )) were elevated in muscle from active adults and associated with cardiorespiratory fitness and muscle oxidative capacity. Acylcarnitines, a potential marker of impaired metabolic health, were elevated in muscle from physically active participants. Surprisingly, despite baseline group difference, acute exercise-induced alterations in whole-body substrate utilization and muscle acylcarnitines and ketone bodies were remarkably similar between groups. Our data identified novel muscle metabolite signatures that associate with the healthy aging phenotype provoked by physical activity and reveal the metabolic responsiveness of muscle to acute endurance exercise is retained with age regardless of activity levels. KEY POINTS: Kynurenine/tryptophan pathway metabolites were impacted by age and physical activity in human muscle, with kynurenine elevated in older muscle, while downstream products kynurenic acid and NAD+ were elevated in exercise-trained muscle regardless of age. Acylcarnitines, a marker of impaired metabolic health when heightened in circulation, was elevated in exercise-trained muscle of young and older adults, suggesting muscle act as a metabolic sink to reduce circulating acylcarnitines observed with unhealthy aging. Despite the phenotypic differences, the exercise-induced response of various muscle metabolite pools, including acylcarnitine and ketone bodies, was similar amongst the groups, suggesting older adults can achieve the metabolic benefits of exercise seen in young counterparts. Abstract figure legend Muscle metabolite profiles at baseline and in response to an acute bout of endurance exercise were examined in three groups: Young Active, Older Active, Older Sedentary. Baseline profiles revealed distinct age- and activity-related metabolite profiles in muscle that associated with clinical and biochemical characteristics of the oxidative phenotype (cardiorespiratory fitness (VO2peak), muscle mitochondrial energetics, and type I fiber type proportion). Specifically, kynurenine-related metabolites (kynurenine, kynurenic acid, and quinolinate) were impacted by age, while nicotinamide adenine dinucleotide (NAD+ ) and acylcarnitines levels were impacted by activity/exercise training. Despite baseline differences, the whole-body and muscle-specific metabolic responses were similarly amongst young and older adults regardless of training status. This article is protected by copyright. All rights reserved.
Keywords: NAD+; aging; ketones; kynurenic acid