Age-Dependent Changes in the Production of Mitochondrial Reactive Oxygen Species in Human Skeletal Muscle

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Mikhail Yu. Vyssokikh^1,2,3,a,a*, Maksim A. Vigovskiy⁴, Vladislav V. Philippov⁴, Yakov R. Boroday⁴, Mariya V. Marey², Olga A. Grigorieva⁴, Tatiana F. Vepkhvadze³, Nadezhda S. Kurochkina³, Ludmila A. Manukhova², Anastasiya Yu. Efimenko⁴, Daniil V. Popov³, and Vladimir P. Skulachev^1#

¹Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia

²National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V. I. Kulakov, 117997 Moscow, Russia

³Institute of Biomedical Problems, Russian Academy of Sciences, 123007 Moscow, Russia

⁴Medical Research and Education Center, Lomonosov Moscow State University, 119192 Moscow, Russia

Received December 12, 2023; Revised January 30, 2024; Accepted February 1, 2024

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A decrease in muscle mass and its functionality (strength, endurance, and insulin sensitivity) is one of the integral signs of aging. One of the triggers of aging is an increase in the production of mitochondrial reactive oxygen species. Our study was the first to examine age-dependent changes in the production of mitochondrial reactive oxygen species related to a decrease in the proportion of mitochondria-associated hexokinase-2 in human skeletal muscle. For this purpose, a biopsy was taken from m. vastus lateralis in 10 young healthy volunteers and 70 patients (26-85 years old) with long-term primary arthrosis of the knee/hip joint. It turned out that aging (comparing different groups of patients), in contrast to inactivity/chronic inflammation (comparing young healthy people and young patients), causes a pronounced increase in peroxide production by isolated mitochondria. This correlated with the age-dependent distribution of hexokinase-2 between mitochondrial and cytosolic fractions, a decrease in the rate of coupled respiration of isolated mitochondria and respiration when stimulated with glucose (a hexokinase substrate). It is discussed that these changes may be caused by an age-dependent decrease in the content of cardiolipin, a potential regulator of the mitochondrial microcompartment containing hexokinase. The results obtained contribute to a deeper understanding of age-related pathogenetic processes in skeletal muscles and open prospects for the search for pharmacological/physiological approaches to the correction of these pathologies.

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KEY WORDS: aging, skeletal muscle, mitochondria, mitochondrial reactive oxygen species, hexokinase

DOI: 10.1134/S0006297924020093

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