Deuterated polyunsaturated fatty acids alleviate in vitro skeletal muscle dysfunction induced by oxidative stress

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 18-carbon 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, muscle-specific protein ligases, and key enzymes involved in mitochondrial energy metabolism. Overall, our study suggests a promising role of D-PUFAs as novel therapeutics to protect against skeletal muscle dysfunction induced by oxidative stress.