Arimbasseri, G. A. | bioRxiv Science

bioRxiv2023

Vitamin D signaling orchestrates skeletal muscle metabolic flexibility by regulating its fuel choice.

Vitamin D deficiency is associated with skeletal muscle pathologies. However, the role of vitamin D signaling in maintenance of muscle function is not well understood. Mice lacking vitamin D receptor (VDR) exhibit severe muscle wasting after weaning and this is associated with accumulation of muscle glycogen and energy deprivation. Here we show that the skeletal muscles of vdr-/- mice exhibit upregulation of fatty acid oxidation pathway and PPAR pathway and are predisposed to utilize fatty acids as the energy source even in a carbohydrate-enriched diet. As a result, fat-enriched diets could alleviate energy deprivation and atrophy of vdr-/- skeletal muscles. However, the complete restoration of muscle mass and systemic metabolism of vdr-/- mice depended on the quality of diets. Despite increasing muscle energy levels, a lard-based high-fat diet (HFD) disrupted glucose homeostasis by specifically inhibiting the insulin synthesis in pancreatic islets. Surprisingly, milk-based high-fat diets (MBD) could restore both muscle mass and pancreatic insulin response. This study reveals a micronutrient-macronutrient interaction network that connects vitamin D signaling with muscle fuel selection and pancreatic insulin response to enable energy homeostasis under different metabolic landscapes.

physiology↗

bioRxiv2021

A vitamin D-RelB/NF-κB pathway limits Chandipura virus multiplication by rewiring the homeostatic state of autoregulatory type 1 interferon-IRF7 signaling

Besides its functions in the skeletomuscular system, vitamin D also promotes protective immunity against viral pathogens. Viral sensing by mammalian cells triggers nuclear activation of RelA/NF-{kappa}B and IRF3 factors, which collaborate in mediating the early induction of antiviral type 1 interferons (T1-IFNs). Autocrine T1-IFN signaling further accumulates otherwise negligibly expressed IRF7 in virus-infected cells that then sustains T1-IFN production in a positive feedback. Surprisingly, prior cell-culture studies revealed that vitamin D actually suppresses signal-induced RelA activation. Indeed, it remains unclear how vitamin D limits viral multiplication in a cell-autonomous manner. Here, we examined the role of vitamin D in controlling cellular infections by the Chandipura virus (CHPV), a cytoplasmic RNA virus implicated in human epidemics. We found that vitamin D conditioning produced an altered cell state less permissive for CHPV multiplication because of the heightened expression of T1-IFNs. It is thought that viruses also induce a distinct RelB/NF-{kappa}B activity, which counteracts RelA-driven T1-IFN expressions in infected cells. Our analyses instead characterized a basal nuclear RelB activity, which was downregulated upon vitamin D-mediated suppression of RelB synthesis. Interestingly, this vitamin D-RelB pathway provoked IRF7-mediated positive autoregulation augmenting constitutive T1-IFN expressions even in the absence of viral infections. Accordingly, RelB deficiency rendered redundant, while IRF7 depletion abrogated antiviral vitamin D actions. In sum, our study suggests that the homeostatic state of the signaling circuitry comprising of the NF-{kappa}B and T1-IFN pathways connects micronutrients to antiviral immunity at the cellular level. Significance statementVitamin D limits viral infections, but the underlying mechanism remains unclear. Linking micronutrients to antiviral immunity, Ratra et al. characterize an immune signaling circuitry engaged by vitamin D that generates a cellular state less permissive to infections by Chandipura virus, a pathogen of public health importance.

immunology↗