Deuterated Polyunsaturated Fatty Acids Alleviate In Vitro Skeletal Muscle Dysfunction Induced by Oxidative Stress

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The paper studied whether deuterated polyunsaturated fatty acids (D-PUFAs) could protect skeletal muscle cells from dysfunction caused by oxidative stress and lipid peroxidation, using in vitro cultured myotubes. The authors compared native hydrogen-containing PUFAs (H-PUFAs) with deuterated forms of arachidonic acid, eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid, and found that D-ARA, D-EPA, D-DPA, and D-DHA reduced ROS-induced lipid peroxidation and protected against ROS-driven impairments in muscle cell function, whereas H-PUFAs increased sensitivity and worsened dysfunction. They also reported that certain deuterated short- and long-chain fatty acids modulated protection against erastin-induced ferroptosis and altered expression of endogenous antioxidant enzymes and muscle-specific protein ligases, with the limitation that all experiments were conducted in vitro. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

ABSTRACT Excessive oxidative stress drives lipid peroxidation and contributes to skeletal muscle atrophy in a range of musculoskeletal diseases. Polyunsaturated fatty acids (PUFAs) are essential components of muscle cell membrane phospholipids and are especially susceptible to peroxidation due to the presence of double bonds. Currently, therapeutic options targeting lipid peroxidation to prevent muscle wasting are limited. Substituting the hydrogen atom at the bis-allylic position with deuterium could conceivably limit lipid peroxidation while retaining enzymatic PUFA metabolism. Here we investigated the potential role of deuterated PUFAs (D-PUFAs) in protecting against muscle cell dysfunction under conditions of elevated oxidative stress. Both native (H-) and deuterated (D-) forms of long chain PUFAs including arachidonic acid (ARA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) stimulated in vitro muscle cell growth and development in the absence of oxidative stress. D-ARA, D-EPA, D-DPA, and D-DHA each protected cultured myotubes against the deleterious effects of direct exposure to reactive oxygen species (ROS) by limiting lipid peroxidation. In contrast, H-ARA, H-EPA, H-DPA, and H-DHA each increased sensitivity to ROS-induced lipid peroxidation and exacerbated oxidative stress-induced muscle cell dysfunction. Deuterated short chain linoleic acid (D-LA), alpha linolenic acid (D-ALA), as well as D-ARA and D-EPA (but not D-DPA or D-DHA) also protected against the deleterious effects of ferroptosis inducer erastin on myogenic differentiation. Finally, D-PUFAs modulated local expression of endogenous antioxidant enzymes and muscle-specific protein ligases. Overall, our study suggests a promising role of D-PUFAs as novel therapeutics to protect against skeletal muscle dysfunction induced by oxidative stress.
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ABSTRACT Excessive oxidative stress drives lipid peroxidation and contributes to skeletal muscle atrophy in a range of musculoskeletal diseases. Polyunsaturated fatty acids (PUFAs) are essential components of muscle cell membrane phospholipids and are especially susceptible to peroxidation due to the presence of double bonds. Currently, therapeutic options targeting lipid peroxidation to prevent muscle wasting are limited. Substituting the hydrogen atom at the bis-allylic position with deuterium could conceivably limit lipid peroxidation while retaining enzymatic PUFA metabolism. Here we investigated the potential role of deuterated PUFAs (D-PUFAs) in protecting against muscle cell dysfunction under conditions of elevated oxidative stress. Both native (H-) and deuterated (D-) forms of long chain PUFAs including arachidonic acid (ARA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) stimulated in vitro muscle cell growth and development in the absence of oxidative stress. D-ARA, D-EPA, D-DPA, and D-DHA each protected cultured myotubes against the deleterious effects of direct exposure to reactive oxygen species (ROS) by limiting lipid peroxidation. In contrast, H-ARA, H-EPA, H-DPA, and H-DHA each increased sensitivity to ROS-induced lipid peroxidation and exacerbated oxidative stress-induced muscle cell dysfunction. Deuterated short chain linoleic acid (D-LA), alpha linolenic acid (D-ALA), as well as D-ARA and D-EPA (but not D-DPA or D-DHA) also protected against the deleterious effects of ferroptosis inducer erastin on myogenic differentiation. Finally, D-PUFAs modulated local expression of endogenous antioxidant enzymes and muscle-specific protein ligases. Overall, our study suggests a promising role of D-PUFAs as novel therapeutics to protect against skeletal muscle dysfunction induced by oxidative stress. Competing Interest Statement The authors have declared no competing interest.

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