Dose-dependent effects of vitamin D on transdifferentiation of skeletal muscle cells to adipose cells

Abstract

Fat infiltration within muscle is one of a number of features of vitamin D deficiency, which leads to a decline in muscle functionality. The origin of this fat is unclear, but one possibility is that it forms from myogenic precursor cells present in the muscle, which transdifferentiate into mature adipocytes. The current study examined the effect of the active form of vitamin D₃, 1,25-dihydroxyvitamin D₃(1,25(OH)₂D₃), on the capacity of the C2C12 muscle cell line to differentiate towards the myogenic and adipogenic lineages. Cells were cultured in myogenic or adipogenic differentiation media containing increasing concentrations (0, 10⁻¹³, 10⁻¹¹, 10⁻⁹, 10⁻⁷or 10⁻⁵ M) of 1,25(OH)₂D₃for up to 6 days and markers of muscle and fat development measured. Mature myofibres were formed in both adipogenic and myogenic media, but fat droplets were only observed in adipogenic media. Relative to controls, low physiological concentrations (10⁻¹³and 10⁻¹¹ M) of 1,25(OH)₂D₃increased fat droplet accumulation, whereas high physiological (10⁻⁹ M) and supraphysiological concentrations (≥10⁻⁷ M) inhibited fat accumulation. This increased accumulation of fat with low physiological concentrations (10⁻¹³and 10⁻¹¹ M) was associated with a sequential up-regulation ofPPARγ2(PPARG) andFABP4mRNA, indicating formation of adipocytes, whereas higher concentrations (≥10⁻⁹ M) reduced all these effects, and the highest concentration (10⁻⁵ M) appeared to have toxic effects. This is the first study to demonstrate dose-dependent effects of 1,25(OH)₂D₃on the transdifferentiation of muscle cells into adipose cells. Low physiological concentrations (possibly mimicking a deficient state) induced adipogenesis, whereas higher (physiological and supraphysiological) concentrations attenuated this effect.