• Cachectic muscle proteome shows decreased OXPHOS and increased acute phase response. • Cancer cachexia is characterized by lowered muscle Nrk2 expression and NAD+ levels. • Blocking activin receptor 2B ligands rescues muscle NAD+ homeostasis in cachexia. • Blocking activin receptor 2B ligands prevents affected protein synthesis in cachexia. • Serpina3n predicts cachexia and cancer-induced APR independently from muscle atrophy.