Disruption of hepatic mitochondrial pyruvate and amino acid metabolism impairs gluconeogenesis and endurance exercise capacity in mice.

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM American journal of physiology. Endocrinology and metabolism Pub Date : 2024-04-01 Epub Date: 2024-02-14 DOI:10.1152/ajpendo.00258.2023
Michael R Martino, Mohammad Habibi, Daniel Ferguson, Rita T Brookheart, John P Thyfault, Gretchen A Meyer, Louise Lantier, Curtis C Hughey, Brian N Finck
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Abstract

Exercise robustly increases the glucose demands of skeletal muscle. This demand is met by not only muscle glycogenolysis but also accelerated liver glucose production from hepatic glycogenolysis and gluconeogenesis to fuel mechanical work and prevent hypoglycemia during exercise. Hepatic gluconeogenesis during exercise is dependent on highly coordinated responses within and between muscle and liver. Specifically, exercise increases the rate at which gluconeogenic precursors such as pyruvate/lactate or amino acids are delivered from muscle to the liver, extracted by the liver, and channeled into glucose. Herein, we examined the effects of interrupting hepatic gluconeogenic efficiency and capacity on exercise performance by deleting mitochondrial pyruvate carrier 2 (MPC2) and/or alanine transaminase 2 (ALT2) in the liver of mice. We found that deletion of MPC2 or ALT2 alone did not significantly affect time to exhaustion or postexercise glucose concentrations in treadmill exercise tests, but mice lacking both MPC2 and ALT2 in hepatocytes (double knockout, DKO) reached exhaustion faster and exhibited lower circulating glucose during and after exercise. Use of 2H/1³C metabolic flux analyses demonstrated that DKO mice exhibited lower endogenous glucose production owing to decreased glycogenolysis and gluconeogenesis at rest and during exercise. Decreased gluconeogenesis was accompanied by lower anaplerotic, cataplerotic, and TCA cycle fluxes. Collectively, these findings demonstrate that the transition of the liver to the gluconeogenic mode is critical for preventing hypoglycemia and sustaining performance during exercise. The results also illustrate the need for interorgan cross talk during exercise as described by the Cahill and Cori cycles.NEW & NOTEWORTHY Martino and colleagues examined the effects of inhibiting hepatic gluconeogenesis on exercise performance and systemic metabolism during treadmill exercise in mice. Combined inhibition of gluconeogenesis from lactate/pyruvate and alanine impaired exercise endurance and led to hypoglycemia during and after exercise. In contrast, suppressing either pyruvate-mediated or alanine-mediated gluconeogenesis alone had no effect on these parameters. These findings provide new insight into the molecular nodes that coordinate the metabolic responses of muscle and liver during exercise.

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肝线粒体丙酮酸和氨基酸代谢紊乱会损害小鼠的糖元生成和耐力运动能力
运动会大量增加骨骼肌对葡萄糖的需求。这种需求不仅要通过肌肉糖原分解来满足,还要通过肝脏糖原分解和糖元生成加速肝脏葡萄糖的生成,为机械运动提供燃料,并防止运动过程中出现低血糖。运动时的肝糖原生成依赖于肌肉和肝脏内部及之间高度协调的反应。具体来说,运动会提高丙酮酸/乳酸或氨基酸等糖元生成前体从肌肉输送到肝脏、被肝脏提取并转化为葡萄糖的速度。在此,我们通过删除小鼠肝线粒体丙酮酸载体 2(MPC2)和/或丙氨酸转氨酶 2(ALT2),研究了中断葡萄糖生成效率和能力对运动表现的影响。我们发现,在跑步机运动测试中,单独缺失 MPC2 或 ALT2 不会显著影响力竭时间或运动后葡萄糖浓度,但肝脏中同时缺失 MPC2 和 ALT2 的小鼠(DKO)力竭速度更快,并且在运动中和运动后表现出更低的循环葡萄糖。利用²H/¹³C代谢通量分析表明,DKO小鼠在休息和运动时由于糖原分解和糖生成减少而表现出较低的内源性葡萄糖生成。伴随着葡萄糖生成减少的是较低的合成代谢通量、催化代谢通量和 TCA 循环通量。总之,这些研究结果表明,肝脏过渡到糖元生成模式对于防止低血糖和维持运动表现至关重要。这些结果还说明,正如卡希尔循环和科里循环所描述的那样,在运动过程中器官间需要相互协作。
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来源期刊
CiteScore
9.80
自引率
0.00%
发文量
98
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Endocrinology and Metabolism publishes original, mechanistic studies on the physiology of endocrine and metabolic systems. Physiological, cellular, and molecular studies in whole animals or humans will be considered. Specific themes include, but are not limited to, mechanisms of hormone and growth factor action; hormonal and nutritional regulation of metabolism, inflammation, microbiome and energy balance; integrative organ cross talk; paracrine and autocrine control of endocrine cells; function and activation of hormone receptors; endocrine or metabolic control of channels, transporters, and membrane function; temporal analysis of hormone secretion and metabolism; and mathematical/kinetic modeling of metabolism. Novel molecular, immunological, or biophysical studies of hormone action are also welcome.
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