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Ranolazine Counteracts Strength Impairment and Oxidative Stress in Aged Sarcopenic Mice.

ABSTRACT: Sarcopenia is defined as the loss of muscle mass associated with reduced strength leading to poor quality of life in elderly people. The decline of skeletal muscle performance is characterized by bioenergetic impairment and severe oxidative stress, and does not always strictly correlate with muscle mass loss. We chose to investigate the ability of the metabolic modulator Ranolazine to counteract skeletal muscle dysfunctions that occur with aging. For this purpose, we treated aged C57BL/6 mice with Ranolazine/vehicle for 14 days and collected the tibialis anterior and gastrocnemius muscles for histological and gene expression analyses, respectively. We found that Ranolazine treatment significantly increased the muscle strength of aged mice. At the histological level, we found an increase in centrally nucleated fibers associated with an up-regulation of genes encoding MyoD, Periostin and Osteopontin, thus suggesting a remodeling of the muscle even in the absence of physical exercise. Notably, these beneficial effects of Ranolazine were also accompanied by an up-regulation of antioxidant and mitochondrial genes as well as of NADH-dehydrogenase activity, together with a more efficient protection from oxidative damage in the skeletal muscle. These data indicate that the protection of muscle from oxidative stress by Ranolazine might represent a valuable approach to increase skeletal muscle strength in elderly populations.

SUBMITTER: Torcinaro A

PROVIDER: S-EPMC9316887 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Ranolazine Counteracts Strength Impairment and Oxidative Stress in Aged Sarcopenic Mice.

Torcinaro Alessio A Cappetta Donato D De Santa Francesca F Telesca Marialucia M Leigheb Massimiliano M Berrino Liberato L Urbanek Konrad K De Angelis Antonella A Ferraro Elisabetta E

Metabolites 20220718 7

Sarcopenia is defined as the loss of muscle mass associated with reduced strength leading to poor quality of life in elderly people. The decline of skeletal muscle performance is characterized by bioenergetic impairment and severe oxidative stress, and does not always strictly correlate with muscle mass loss. We chose to investigate the ability of the metabolic modulator Ranolazine to counteract skeletal muscle dysfunctions that occur with aging. For this purpose, we treated aged C57BL/6 mice wi ...[more]

PMID: 35888787

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Project description:RationaleMitochondrial oxidative stress (mitoOS) has been shown to be increased in various cell types in human atherosclerosis and with aging. However, the role of cell type-specific mitoOS in atherosclerosis in the setting of advanced age and the molecular mechanisms remains to be determined in vivo.ObjectiveThe aim of this study was to examine the role of myeloid cell mitoOS in atherosclerosis in aged mice.Approach and resultsLethally irradiated low-density lipoprotein receptor-deficient mice (Ldlr-/-) were reconstituted with bone marrow from either wild-type or mitochondrial catalase (mCAT) mice. mCAT transgenic mice contain ectopically expressed human catalase gene in mitochondria, which reduces mitoOS. Starting at the age of 36 weeks, mice were fed the Western-type diet for 16 weeks. We found that mitoOS in lesional myeloid cells was suppressed in aged mCAT→Ldlr-/- chimeric mice compared with aged controls, and this led to a significant reduction in aortic root atherosclerotic lesion area despite higher plasma cholesterol levels. Neutrophil extracellular traps (NETs), a proinflammatory extracellular structure that contributes to atherosclerosis progression, were significantly increased in the lesions of aged mice compared with lesions of younger mice. Aged mCAT→Ldlr-/- mice had less lesional neutrophils and decreased NETs compared with age-matched wild-type→Ldlr-/- mice, whereas young mCAT→ and wild-type→Ldlr-/- mice had comparable numbers of neutrophils and similar low levels of lesional NETs. Using cultured neutrophils, we showed that suppression of mitoOS reduced 7-ketocholesterol-induced NET release from neutrophils of aged but not younger mice.ConclusionsMitoOS in lesional myeloid cells enhanced atherosclerosis development in aged mice, and this enhancement was associated with increased lesional NETs. Thus, mitoOS-induced NET formation is a potentially new therapeutic target to prevent atherosclerosis progression during aging.

Project description:IntroductionWhen confronted to stress or pathological conditions, the mitochondria overproduce reactive species that participate in the cellular dysfunction. These organelles are however difficult to target with antioxidants. A feature of mitochondria that can be used for this is the negatively charged compartments they form. Most of mitochondrion-targeting antioxidants are therefore cationic synthetic molecules. Our hypothesis is that such mitochondriotropic traits might also exists in natural molecules.AimWe tested here whether sinapine, a natural phenolic antioxidant-bearing a permanent positive charge, can target mitochondria to modulate mitochondrial oxidative stress.MethodsExperiments were performed in-vitro, in-cellulo, ex-vivo, and in-vivo, using cardiac tissue. The sinapic acid -lacking the positively-charged-choline-moiety present in sinapine-was used as a control. Sinapine entry into mitochondria was investigated in-vivo and in cardiomyocytes. We used fluorescent probes to detect cytosolic (H2DCFDA) and mitochondrial (DHR123) oxidative stress on cardiomyocytes induced with either hydrogen peroxide (H2O2) or antimycin A, respectively. Finally, ROS production was measured with DHE 10 min after ischemia-reperfusion (IR) on isolated heart, treated or not with sinapine, sinapic acid or with a known synthetic mitochondrion-targeted antioxidant (mitoTempo).ResultsWe detected the presence of sinapine within mitochondria in-vitro, after incubation of isolated cardiomyocytes, and in-vivo, after oral treatment. The presence of sinapic acid was not detected in the mitochondria. Both the sinapine and the sinapic acid limited cytosolic oxidative stress in response to H2O2. Only sinapine was able to blunt oxidative stress resulting from antimycin A-induced mtROS. Both mitoTempo and sinapine improved cardiac functional recovery following IR. This was associated with lower ROS production within the cardiac tissue.ConclusionSinapine, a natural cationic hydrophilic phenol, commonly and substantially found in rapeseed species, effectively (i) enters within the mitochondria, (ii) selectively decreases the level of mitochondrial oxidative stress and, (iii) efficiently limits ROS production during cardiac ischemia-reperfusion.

Dataset Information

Ranolazine Counteracts Strength Impairment and Oxidative Stress in Aged Sarcopenic Mice.

Publications

Ranolazine Counteracts Strength Impairment and Oxidative Stress in Aged Sarcopenic Mice.

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