The conversion of skeletal muscle fiber from fast twitch to slow‐twitch is important for sustained and tonic contractile events, maintenance of energy homeostasis, and the alleviation of fatigue. Skeletal muscle remodeling is effectively induced by endurance or aerobic exercise, which also generates several tricarboxylic acid ( TCA ) cycle intermediates, including succinate. However, whether succinate regulates muscle fiber‐type transitions remains unclear. Here, we found that dietary succinate supplementation increased endurance exercise ability, myosin heavy chain I expression, aerobic enzyme activity, oxygen consumption, and mitochondrial biogenesis in mouse skeletal muscle. By contrast, succinate decreased lactate dehydrogenase activity, lactate production, and myosin heavy chain II b expression. Further, by using pharmacological or genetic loss‐of‐function models generated by phospholipase Cβ antagonists, SUNCR 1 global knockout, or SUNCR 1 gastrocnemius‐specific knockdown, we found that the effects of succinate on skeletal muscle fiber‐type remodeling are mediated by SUNCR 1 and its downstream calcium/ NFAT signaling pathway. In summary, our results demonstrate succinate induces transition of skeletal muscle fiber via SUNCR 1 signaling pathway. These findings suggest the potential beneficial use of succinate‐based compounds in both athletic and sedentary populations.

Beneficial effects of resistance exercise on metabolic health and particularly muscle hypertrophy and fat loss are well established, but the underlying chemical and physiological mechanisms are not fully understood. Here, we identified a myometabolite‐mediated metabolic pathway that is essential for the beneficial metabolic effects of resistance exercise in mice. We showed that substantial accumulation of the tricarboxylic acid cycle intermediate α‐ketoglutaric acid (AKG) is a metabolic signature of resistance exercise performance. Interestingly, human plasma AKG level is also negatively correlated with BMI. Pharmacological elevation of circulating AKG induces muscle hypertrophy, brown adipose tissue (BAT) thermogenesis, and white adipose tissue (WAT) lipolysis in vivo. We further found that AKG stimulates the adrenal release of adrenaline through 2‐oxoglutarate receptor 1 (OXGR1) expressed in adrenal glands. Finally, by using both loss‐of‐function and gain‐of‐function mouse models, we showed that OXGR1 is essential for AKG‐mediated exercise‐induced beneficial metabolic effects. These findings reveal an unappreciated mechanism for the salutary effects of resistance exercise, using AKG as a systemically derived molecule for adrenal stimulation of muscle hypertrophy and fat loss.

The combination of the LNR and pN status provides a valuable help with prognosis. However, these results must be evaluated further in a large prospective randomized clinical trial.

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Running title: α-ketoglutaric acid stimulates lipolysis through OXGR1 31 32 Conflict of interest statement 33The authors have declared that no conflict of interest exists. 34 35 36 37 38 39 40 41 42 43 44 3 Summary: Beneficial effects of resistance exercise on metabolic health and particularly muscle 45hypertrophy and fat loss are well established, but the underlying chemical and physiological 46 mechanisms are not fully understood. Here we identified a myometabolite-mediated metabolic 47 pathway that is essential for the beneficial metabolic effects of resistance exercise in vivo. We showed 48 that substantial accumulation of the tricarboxylic acid cycle intermediate α-ketoglutaric acid (AKG) is 49 a metabolic signature of resistance exercise performance. Interestingly, human plasma AKG level is 50 also negatively correlated with BMI. Pharmacological elevation of circulating AKG induces muscle 51 hypertrophy, brown adipose tissue (BAT) thermogenesis, and white adipose tissue (WAT) lipolysis in 52 vivo. We further found that AKG stimulates the adrenal release of adrenaline through 2-oxoglutarate 53 receptor 1 (OXGR1) expressed in adrenal glands. Finally, by using both loss-of-function and 54 gain-of-function mouse models, we showed that OXGR1 is essential for AKG-mediated 55 exercise-induced beneficial metabolic effects. These findings reveal an unappreciated mechanism for 56 the salutary effects of resistance exercise, using AKG as a systemically-derived molecule for adrenal 57 stimulation of muscle hypertrophy and fat loss. 58 59 Keywords: AKG/lipolysis /obesity/OXGR1/thermogenesis. 60 61 62 63 64 5 provide signatures of endurance exercise performance and cardiovascular disease susceptibility, and 88also identify molecular pathways that may modulate the salutary effects on cardiovascular function. 89However, very few metabolomics data is available for resistance exercise (Berton et al, 2017; Li et al, 90 2012), and the underlying chemical and physiological mechanisms for the stimulatory effects of 91 resistance exercise on fat loss and muscle hypertrophy are not fully understood. Our goal is to identify 92 the essential mediator for the beneficial metabolic effects of resistance exercise and provide potential 93 therapeutic strategies to mimic the health effects of resistance exercise to combat obesity. 94 95Emerging evidence has identified skeletal muscle as secretory organs in regulating energy 96 homeostasis and obesity progression in other tissues (Ibrahim et al, 2017; Rai & Demontis, 2016). 97Exercise can induce systemic metabolic effects either via changes in the mass and metabolic demand 98 of muscle or via the release of muscle-derived cytokines (myokines) and metabolites (myometabolites) 99