B cell deficiency limits exercise capacity by remodeling liver glutamate metabolism.

Abstract

B cells are an essential component of humoral immunity, and B cell depletion therapies have clinically succeeded in eliminating cancerous B cells and treating autoimmune diseases. Here, we report an immune-independent function of B cells that spatially and metabolically drives exercise capacity. During exercise, B cell deficiency reduces transforming growth factor (TGF)-β1 production, which alters hepatic glutamate metabolism and decreases blood and muscle glutamate. Mechanistically, B cell-derived TGF-β1 transcriptionally upregulates hepatic glutaminase 2 (GLS2) and solute carrier family 7 member 5 (SLC7A5) expression, increasing glutamine catabolism and thus glutamate production in the liver. The resulting increase in glutamate fosters skeletal muscle calcium oscillations, calmodulin-dependent protein kinase (CaMK) kinase activity, and mitochondrial biogenesis, thereby improving exercise performance. Thus, we identify a metabolite-driven liver-muscle connection that regulates exercise capacity, linking B cell function to skeletal muscle calcium signaling via alteration of hepatic glutamate metabolism.