Abstract
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 IIb expression. Further, by using pharmacological or genetic loss‐of‐function models generated by phospholipase Cβ antagonists, SUNCR1 global knockout, or SUNCR1 gastrocnemius‐specific knockdown, we found that the effects of succinate on skeletal muscle fiber‐type remodeling are mediated by SUNCR1 and its downstream calcium/NFAT signaling pathway. In summary, our results demonstrate succinate induces transition of skeletal muscle fiber via SUNCR1 signaling pathway. These findings suggest the potential beneficial use of succinate‐based compounds in both athletic and sedentary populations.
Highlights
The conversion of skeletal muscle fiber from fast twitch to slowtwitch is important for sustained and tonic contractile events, maintenance of energy homeostasis, and the alleviation of fatigue
We found that succinate-supplemented diet increased serum SUA level (Fig 1A) but had no effects on the body weight gain (Fig 1B), food intake (Fig EV1A), fat mass (Fig 1C), lean mass (Fig 1D), gastrocnemius muscle index (Fig 1E), or liver index (Fig EV1B)
Skeletal muscle fiber types are distinguished by myosin heavy chain (MyHC) isoforms [26], metabolic enzyme activity [6], mitochondrial number [27], and contractile properties [28]
Summary
The conversion of skeletal muscle fiber from fast twitch to slowtwitch 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 generates several tricarboxylic acid (TCA) cycle intermediates, including succinate. 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 using pharmacological or genetic loss-of-function models generated by phospholipase Cb antagonists, SUNCR1 global knockout, or SUNCR1 gastrocnemius-specific knockdown, we found that the effects of succinate on skeletal muscle fiber-type remodeling are mediated by SUNCR1 and its downstream calcium/NFAT signaling pathway. Our results demonstrate succinate induces transition of skeletal muscle fiber via SUNCR1 signaling pathway. These findings suggest the potential beneficial use of succinate-based compounds in both athletic and sedentary populations
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