The orphan nuclear receptor Nr2f6 impairs skeletal muscle oxidative capacity and regulates muscle mass in mice

Abstract

The maintenance of skeletal muscle plasticity upon changes in the environment, nutrient supply, and exercise depends on regulatory mechanisms that couple structural and metabolic adaptations. However, the transcriptional control of both processes by nuclear receptors (NR) remains underexplored. Nr2f6 is an orphan NR and a key regulator of metabolism and differentiation. Nonetheless, its role in muscle biology remains elusive. Here, we report, for the first time, the effects of Nr2f6 modulation in skeletal muscle in vivo and in vitro. Depletion of Nr2f6 increased myocyte’s oxidative capacity and sharply attenuated lipid-induced cell death, which was associated with direct derepression of uncoupling protein 3 and PGC-1α promoters’ transactivation. Conversely, Nr2f6 overexpression in the tibialis anterior induced atrophy and hypoplasia, accompanied by impairment of force production and the establishment of a molecular signature of inflammation, and a decrease in genes involved in oxidative metabolism and contraction. Additionally, global transcriptomics showed that Nr2f6 upregulated core components of the cell division machinery and repressed myogenesis genes thus decoupling myoblast proliferation from differentiation. Collectively, our findings define a novel role for Nr2f6 as a molecular transducer maintaining the balance between skeletal muscle contractile function and oxidative capacity, with implications for metabolic diseases and myopathies treatment.