Introduction: Postnatal activin/myostatin type IIB receptor (ActRIIB) blockade increases skeletal muscle mass and strength but also increases muscle fatigability and impairs oxidative metabolism. The objective of this study was to determine in vivo whether this increased fatigability is due to energy supply limitation. Methods: The impact of 8-week ActRIIB blockade with soluble receptor (sActRIIB-Fc) on muscle function and adenosine triphosphate (ATP) fluxes was investigated noninvasively by using multimodal magnetic resonance and indirect calorimetry measurements in wild-type mice. Results: Activin/myostatin type IIB receptor blockade reduced (−41%) the muscle apparent mitochondrial capacity and increased (+11%) the basal body energy expenditure. During a fatiguing exercise, ActRIIB blockade decreased both oxidative ATP production rate (−32%) and fatigue resistance (−36%), but these changes affected neither the total ATP production rate nor the contractile ATP cost. Discussion: These findings demonstrate that the increased fatigability after ActRIIB blockade is not due to limitation in energy supply and/or disturbance in contractile ATP cost.