Exploring heme-iron and energy metabolism in skeletal muscle-specific Flvcr1a knockout mice

Feline leukemia virus subgroup C receptor 1a (FLVCR1a) is a plasma membrane heme exporter that, by removing the intracellular excess of heme, limits the feedback inhibitory effects of heme on its own production, thus sustaining heme biosynthesis. Being part of the heme synthesis-export functional axis, heme export by FLVCR1a has been reported to sustain the tricarboxylic acid cycle (TCA) flux and the electron transport chain (ETC) activity in tumors. However, the relevance of the heme synthesis-export system in normal tissues has never been addressed. Here we generate skeletal muscle-specific Flvcr1a-null mice and analyze the impact of disrupted heme synthesis-export axis in this tissue, which is one of the major heme-consuming body compartments. Metabolic data obtained in gastrocnemius show that, upon deletion of Flvcr1a, the activity of TCA cycle enzymes and ETC complexes is increased, along with glutaminolysis and fatty-acid beta oxidation. Conversely, the activity of glycolytic enzymes is reduced. Flvcr1a deletion also affects muscle morphology. The number of fibers expressing the slow-oxidative myosin heavy chain isoform is increased in Flvcr1a-null mice compared to controls and the average cross-sectional fibers’ area is reduced, which is another feature of slow-oxidative fibers. In motor behavior tests, Flvcr1a knockout mice show worse performance compared to controls, a phenotype exacerbated by aging. Collectively, these results hint that FLVCR1a is involved in the regulation of energetic metabolism in skeletal muscle, and that the heme synthesis-export system is important to maintain proper muscle function.