Lactate as an Exercise Mimetic: Mitigating Disuse Atrophy and Improving Muscle Endurance in Aging SAMP8 Mice

Lactate, historically considered a metabolic byproduct, has emerged as a key regulator of muscle physiology and metabolism. This study explores its potential as an exercise mimetic to counteract disuse muscle atrophy (DMA) in aging skeletal muscle using a hindlimb suspension model in senescence-accelerated prone 8 (SAMP8) mice. The mice were divided into four groups: Control, lactate-treated control, hindlimb suspension, and hindlimb suspension with lactate intervention. Lactate administration significantly preserved gastrocnemius muscle mass, restored muscle strength, and attenuated oxidative muscle fiber atrophy. Electrophoretic and histological analyses revealed an increase in MyHC I expression, indicating a protective effect on oxidative muscle fibers. Functional assessments showed that lactate improved muscle endurance and contractile force, while metabolomic profiling identified significant changes in energy metabolism, amino acid metabolism, and protein synthesis pathways. Specifically, lactate intervention improved impaired branched-chain amino acid metabolism, suggesting improved protein synthesis and recovery. In addition, lactate enhanced Cori cycle activity, upregulated hepatic lactate transporters, and increased lactate dehydrogenase B enzymatic activity, facilitating efficient lactate metabolism and gluconeogenesis. These results provide new insights into the role of lactate as a metabolic regulator and highlight its potential as a therapeutic intervention to combat exercise-induced muscle wasting and preserve muscle function in aging and immobilized individuals.

乳酸（Lactate）曾被视为一种代谢副产物，如今已成为调控肌肉生理学与代谢的关键因子。本研究以快速老化易感8（SAMP8）小鼠的后肢悬吊模型（hindlimb suspension model）为实验体系，探讨其作为运动模拟剂（exercise mimetic）对抗衰老骨骼肌废用性肌肉萎缩（disuse muscle atrophy, DMA）的潜力。实验将小鼠分为四组：对照组、乳酸处理对照组、后肢悬吊组以及联合乳酸干预的后肢悬吊组。乳酸给药可显著维持腓肠肌（gastrocnemius muscle）质量、恢复肌肉力量，并减轻氧化型肌纤维（oxidative muscle fiber）的萎缩。电泳与组织学分析显示，肌球蛋白重链I型（MyHC I）的表达水平显著升高，表明乳酸对氧化型肌纤维具有保护作用。功能评估结果表明，乳酸可改善肌肉耐力与收缩力量；代谢组学分析（metabolomic profiling）则揭示了能量代谢、氨基酸代谢及蛋白质合成通路的显著变化。具体而言，乳酸干预可改善受损的支链氨基酸（branched-chain amino acid）代谢，提示其可促进蛋白质合成与损伤修复。此外，乳酸可增强科里循环（Cori cycle）活性、上调肝脏乳酸转运体（hepatic lactate transporters）的表达，并提升乳酸脱氢酶B（lactate dehydrogenase B）的酶活性，从而促进高效的乳酸代谢与糖异生（gluconeogenesis）过程。本研究结果为乳酸作为代谢调控因子的作用机制提供了全新视角，并凸显了其作为治疗干预手段的潜力，可用于对抗运动诱导的肌肉流失，维持衰老与肢体制动个体的肌肉功能。