NAD+ limitation and α-ketoglutarate depletion define cancer induced muscle atrophy

Tumour-host crosstalk is an emerging hallmark of malignancy. It is increasingly recognised that cancer alters non-tumour bearing distant organs, with important consequences for disease progression and survival. Skeletal muscle loss, a defining feature of cancer-associated cachexia, contributes to morbidity and reduced quality of life, yet its underlying mechanisms remain poorly understood. In this study we analysed the secretome of pancreatic cancer cells and identified a metabolite-driven signal that induces myotube atrophy. Our data suggests that atrophy, which seems to involve cytoskeletal stress and increased myosin contractility, arises from cancer cell-dependent reductive metabolic rewiring. Pancreatic cancer cells conditioned their environment with elevated levels of lactate, generating a lactate-rich extracellular milieu that decrease the NAD+/NADH ratio in myotubes. This redox imbalance impaired oxidative metabolism, decreasing -ketoglutarate (KG) levels and disrupted KG-dependent processes. Restoration of NAD+ or KG levels rescued myotube atrophy. Skeletal muscle from cancer-associated cachexia mouse models exhibited reduced KG levels. Collectively, these findings identify a targetable metabolite-mediated mechanism of tumour-muscle crosstalk.