Blood vessel epicardial substance (BVES) gene (also known as Popeye domain containing protein 1 or POPDC1) encodes a cAMP-binding transmembrane protein, belonging to the Popeye domain containing (POPDC) protein family, which contains two other members POPDC2 and POPDC3. All POPDC proteins are highly expressed in striated muscles. Genetic mutations in BVES were identified in patients with limb girdle muscular dystrophy type R25 (LGMDR25) and cardiac arrhythmia. However, the pathogenesis mechanism underlying LGMDR25 remains elusive. We generated a mouse model of LGMDR25 with deletion of the entire coding sequence of Bves. The Bves-deleted mice developed muscular dystrophy with reduced muscle mass and impaired muscle performance, whereas adeno-associated virus 9 (AAV9)-mediated BVES gene transfer in Bves-deficient skeletal muscle reverses these defects. Immunoprecipitation-mass spectrometry identified ADCY9 as a novel interactor of BVES, which negatively regulates ADCY9’s activity. Disruption of BVES-mediated control of cAMP signaling leads to an increased protein kinase A (PKA) signaling cascade, thereby promoting FoxO-mediated protein degradation via the ubiquitin-proteasome system (UPS). Pharmacological inhibition of UPS by bortezomib, an anti-cancer drug approved by Food and Drug Administration (FDA) for the treatment of multiple myeloma and mantle cell lymphoma, improved muscle mass and function in Bves-KO mice. Our study reveals that BVES plays an important role in maintaining muscle homeostasis via regulating ADCY9-mediated cAMP signaling.