In this issue of Cell, Mao et al. reveal that B cells play an unexpected, immune-independent role in exercise physiology by facilitating multi-organ communication. Secreting TGF-β1, they transcriptionally reprogram hepatic glutamine metabolism via GLS2 and SLC7A5, preserving skeletal muscle glutamate levels, which sustain mitochondrial function, Ca2⁺ signaling, and ATP production, enhancing exercise capacity.