Abstract
Enhanced oxidative stress has been associated with muscle mitochondrial changes and metabolic disorders. Thus, it might be a good strategy to decrease oxidative stress and improve mitochondrial changes in skeletal muscle. In the present study, we investigate the role of the most biologically active metabolite of vitamin D, 1,25-dihyroxyvitamin D (1,25(OH)2D) in oxidative stress and mitochondrial changes in tertiary butyl-hydrogen (tBHP)-treated C2C12 muscle cells. Differentiated C2C12 muscle cells were pretreated with tBHP, followed by 1,25(OH)2D for additional 24 h. An exogenous inducer of oxidative stress, tBHP significantly increased oxidative stress, lipid peroxidation, intracellular damage, and cell death which were reversed by 1,25(OH)2D in C2C12 myotubes. 1.25(OH)2D improves tBHP-induced mitochondrial morphological changes such as swelling, irregular cristae, and smaller size and number, as observed by transmission electron microscope. In addition, 1,25(OH)2D treatment increases mtDNA contents as well as gene expression involved in mitochondrial biogenesis such as PGC1α, NRF1, and Tfam. Significant increments in mRNA levels related to antioxidant enzymes such as Nrf2, HMOX1, and TXNRD1, myogenic differentiation markers including myoglobin, muscle creatine kinase (MCK), and MHCІ and ІІ, and vitamin D metabolism such as CYP24, CYP27, and vitamin D receptor (VDR) were found in 1,25(OH)2D-treated myotubes. Moreover, upon t-BHP-induced oxidative stress, significant incremental changes in nicotinamide adenine dinucleotide (NAD) levels, activities of AMP-activated protein kinase (AMPK)/sirtulin 1 (SIRT1), and SIRT1 expression were noted in 1,25(OH)2D-treated C2C12 muscle cells. Taken together, these results suggest the observed potent inhibitory effect of 1,25(OH)2D on muscle oxidative stress and mitochondrial dynamics might be at least involved in the activation of AMPK and SIRT1 activation in muscle cells.
Highlights
Oxidative stress—an imbalance between the production of reactive oxygen species (ROS) and antioxidant capacity—has been implicated in the pathophysiology of obesity and its-associated metabolic diseases including hypertension, hyperglycemia, and dyslipidemia [1,2]
Overproduction of ROS leads to irreversible modifications such as cellular injury and decreased antioxidant capacity in cellular components [3], which in turn contributes to mitochondrial dysfunction, characterized as diminished mitochondrial biogenesis, altered membrane potential, and decreased mitochondria number, and excessive oxidative production [4,5]
The present study demonstrates that 1,25(OH)2D significantly prevented tertiary butyl-hydrogen peroxide (tBHP)-induced ROS, lipid peroxidation, cellular damage, and cell death in C2C12 muscle cells
Summary
Oxidative stress—an imbalance between the production of reactive oxygen species (ROS) and antioxidant capacity—has been implicated in the pathophysiology of obesity and its-associated metabolic diseases including hypertension, hyperglycemia, and dyslipidemia [1,2]. Overproduction of ROS leads to irreversible modifications such as cellular injury and decreased antioxidant capacity in cellular components [3], which in turn contributes to mitochondrial dysfunction, characterized as diminished mitochondrial biogenesis, altered membrane potential, and decreased mitochondria number, and excessive oxidative production [4,5]. Mitochondrial function, and oxidative capacity has been reported in obesity and obesity-associated. The decrease of ROS and the improvement of mitochondria biogenesis and function in skeletal muscle might be the potential targets for the prevention and/or treatment of metabolic complications. A close relationship between low vitamin D status and reduced muscle strength, mass, and function has been reported [12,13,14]. Several intervention studies demonstrate that vitamin D supplementation decreases the incidence of falls with enhanced muscle strength and muscular function [15,16,17].
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