Vitamin D deficiency is associated with symptoms of skeletal muscle myopathy including muscle weakness and fatigue. Recently, vitamin D-related metabolites have been linked to the maintenance of mitochondrial function within skeletal muscle. However, current evidence is limited to in vitro models and the effects of diet-induced vitamin D deficiency upon skeletal muscle mitochondrial function in vivo have received little attention. In order to examine the role of vitamin D in the maintenance of mitochondrial function in vivo, we utilised an established model of diet-induced vitamin D deficiency in C57BL/6J mice. Mice were either fed a control diet (2200 IU/kg i.e. vitamin D replete) or a vitamin D-deplete (0 IU/kg) diet for periods of 1, 2 and 3 months. Gastrocnemius muscle mitochondrial function and ADP sensitivity were assessed via high-resolution respirometry and mitochondrial protein content via immunoblotting. As a result of 3 months of diet-induced vitamin D deficiency, respiration supported via complex I + II (CI + IIP) and the electron transport chain (ETC) were 35 and 37% lower when compared to vitamin D-replete mice (P < 0.05). Despite functional alterations, citrate synthase activity, AMPK phosphorylation, mitofilin, OPA1 and ETC subunit protein content remained unchanged in response to dietary intervention (P > 0.05). In conclusion, we report that 3 months of diet-induced vitamin D deficiency reduced skeletal muscle mitochondrial respiration in C57BL/6J mice. Our data, when combined with previous in vitro observations, suggest that vitamin D-mediated regulation of mitochondrial function may underlie the exacerbated muscle fatigue and performance deficits observed during vitamin D deficiency.
Oxidative stress is a major hallmark of COPD, contributing to inflammatory signaling, corticosteroid resistance, DNA damage, and accelerated lung aging and cellular senescence. Evidence suggests that oxidative damage is not solely due to exogenous exposure to inhaled irritants, but also endogenous sources of oxidants in the form of reactive oxygen species (ROS). Mitochondria, the major producers of ROS, exhibit impaired structure and function in COPD, resulting in reduced oxidative capacity and excessive ROS production. Antioxidants have been shown to protect against ROS-induced oxidative damage in COPD, by reducing ROS levels, reducing inflammation, and protecting against the development of emphysema. However, currently available antioxidants are not routinely used in the management of COPD, suggesting the need for more effective antioxidant agents. In recent years, a number of mitochondria-targeted antioxidant (MTA) compounds have been developed that are capable of crossing the mitochondria lipid bilayer, offering a more targeted approach to reducing ROS at its source. In particular, MTAs have been shown to illicit greater protective effects compared to non-targeted, cellular antioxidants by further reducing apoptosis and offering greater protection against mtDNA damage, suggesting they are promising therapeutic agents for the treatment of COPD. Here, we review evidence for the therapeutic potential of MTAs as a treatment for chronic lung disease and discuss current challenges and future directions.
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