Statin treatment reduces leucine turnover, but does not affect endogenous production of beta-hydroxy-beta-methylbutyrate (HMB)

Martin Hagve; Suzette L Pereira; Dillon K Walker; Marielle P K J Engelen; Nicolaas E P Deutz

doi:10.1016/j.metabol.2024.155920

Statin treatment reduces leucine turnover, but does not affect endogenous production of beta-hydroxy-beta-methylbutyrate (HMB)

Metabolism. 2024 Apr 25:155920. doi: 10.1016/j.metabol.2024.155920. Online ahead of print.

Authors

Martin Hagve¹, Suzette L Pereira², Dillon K Walker³, Marielle P K J Engelen⁴, Nicolaas E P Deutz⁵

Affiliations

¹ Center for Translational Research in Aging & Longevity, Dept. Health and Kinesiology, Texas A&M University, College Station, TX, USA. Electronic address: martin.hagve@gmail.com.
² Abbott Nutrition, Research and Development, Columbus, OH, USA. Electronic address: suzette.pereira@abbott.com.
³ Center for Translational Research in Aging & Longevity, Dept. Health and Kinesiology, Texas A&M University, College Station, TX, USA.
⁴ Center for Translational Research in Aging & Longevity, Dept. Health and Kinesiology, Texas A&M University, College Station, TX, USA. Electronic address: mpkj.engelen@ctral.org.
⁵ Center for Translational Research in Aging & Longevity, Dept. Health and Kinesiology, Texas A&M University, College Station, TX, USA. Electronic address: nep.deutz@ctral.org.

PMID: 38677663
DOI: 10.1016/j.metabol.2024.155920

Abstract

Background: 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, resulting in mitochondrial dysfunction. HMG-CoA is a metabolite of leucine and its corresponding keto acid α-ketoisocaproic acid (KIC) and beta-hydroxy-beta-methylbutyrate (HMB), however little is known about the changes in the metabolism of leucine and its metabolites in response to statins.

Objective: 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).

Design: 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.

Results: 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.

Conclusions: 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.

Keywords: Amino acids; Isotope pulse; Leucine; Statins; beta-hydroxy-beta-methylbutyrate.