Center for Translational Research in Aging & Longevity, Dept. Health and Kinesiology, Texas A&M University, College Station, TX, USA.
Abbott Nutrition, Research and Development, Columbus, OH, USA.
Metabolism. 2024 Jul;156:155920. doi: 10.1016/j.metabol.2024.155920. Epub 2024 Apr 25.
Statins, or hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, are one of the most commonly prescribed medications for lowering cholesterol. Myopathic side-effects ranging from pain and soreness to critical rhabdomyolysis are commonly reported and often lead to discontinuation. The pathophysiological mechanism is, in general, ascribed to a downstream reduction of Coenzyme Q10 synthesis. HMG-CoA is a metabolite of leucine and its corresponding keto acid α-ketoisocaproic acid (KIC) and β-hydroxy-β-methylbutyrate (HMB), however, little is known about the changes in the metabolism of leucine and its metabolites in response to statins.
We aimed to investigate if statin treatment has implications on the upstream metabolism of leucine to KIC and HMB, as well as on other branched chain amino acids (BCAA).
12 hyperlipidemic older adults under statin treatment were recruited. The study was conducted as a paired prospective study. Included participants discontinued their statin treatment for 4 weeks before they returned for baseline measurements (before). Statin treatment was then reintroduced, and the participants returned for a second study day 7 days after reintroduction (after statin). On study days, participants were injected with stable isotope pulses for measurement of the whole-body production (WBP) of all BCAA (leucine, isoleucine and valine), along with their respective keto acids and HMB.
We found a reduced leucine WBP (22 %, p = 0.0033), along with a reduction in valine WBP (13 %, p = 0.0224). All other WBP of BCAA and keto acids were unchanged. There were no changes in the WBP of HMB.
Our study shows that statin inhibition of HMG-CoA reductase has an upstream impact on the turnover of leucine and valine. Whether this impairment in WBP of leucine may contribute to the known pathophysiological side effects of statins on muscle remains to be further investigated.
他汀类药物，或羟甲基戊二酰辅酶 A（HMG-CoA）还原酶抑制剂，是最常用于降低胆固醇的药物之一。从疼痛和酸痛到严重横纹肌溶解的肌肉疾病副作用经常被报道，并经常导致停药。病理生理学机制通常归因于辅酶 Q10 合成的下游减少。HMG-CoA 是亮氨酸及其相应的酮酸 α-酮异己酸（KIC）和 β-羟基-β-甲基丁酸（HMB）的代谢物，然而，关于亮氨酸及其代谢物对他汀类药物的代谢变化知之甚少。
我们旨在研究他汀类药物治疗是否会影响 KIC 和 HMB 上游亮氨酸的代谢，以及其他支链氨基酸（BCAA）。
招募了 12 名接受他汀类药物治疗的高脂血症老年人。该研究作为配对前瞻性研究进行。纳入的参与者在返回进行基线测量（之前）之前停止他汀类药物治疗 4 周。然后重新引入他汀类药物治疗，参与者在重新引入后第 7 天返回进行第二次研究日（之后）。在研究日，参与者接受稳定同位素脉冲注射，以测量所有 BCAA（亮氨酸、异亮氨酸和缬氨酸）及其相应酮酸和 HMB 的全身生成率（WBP）。
我们发现亮氨酸 WBP 降低（22%，p=0.0033），同时缬氨酸 WBP 降低（13%，p=0.0224）。所有其他 BCAA 和酮酸的 WBP 均无变化。HMB 的 WBP 没有变化。
我们的研究表明，他汀类药物抑制 HMG-CoA 还原酶对亮氨酸和缬氨酸的周转率有上游影响。WBP 中亮氨酸的这种损伤是否可能导致已知的他汀类药物对肌肉的病理生理学副作用还有待进一步研究。
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