An NAD+-responsive adipose signal coordinates inter-organ defense against muscle atrophy.

Loss of skeletal muscle mass is a major driver of frailty and disability, yet how systemic metabolic cues protect muscle integrity remains unclear. We identify Serpina3n, an adipose-derived adipokine, as a key mediator of the protective effects of nicotinamide adenine dinucleotide (NAD+) supplementation against muscle atrophy. Elevation of NAD+ in adipose tissue activates signal transducer and activator of transcription (STAT)1-dependent transcription of Serpina3n, leading to its systemic release and muscle protection across models of aging, disuse, and cancer cachexia. In muscle, Serpina3n preserves pyruvate carboxylase protein level, promoting anaplerosis, oxidative metabolism, and protein synthesis. These findings define an NAD+-responsive adipose-to-muscle signaling axis that links metabolic status to tissue preservation, defining a systemic mechanism by which inter-organ communication maintains muscle integrity and suggesting potential strategies to counteract muscle degeneration.