Pancreatic cancer-driven muscle atrophy traced to NAD+ loss and alpha-ketoglutarate depletion
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Cachexia, the muscle-wasting syndrome that accompanies many cancers, lacks targeted treatments. New preclinical work identifies a mechanism by which pancreatic cancer drives muscle atrophy: tumour cells secrete lactate that lowers the NAD+/NADH ratio in myotubes, impairing oxidative metabolism and depleting alpha-ketoglutarate. This depletion triggers cytoskeletal stress and increased myosin contractility, leading to myotube wasting. Restoring NAD+ or alpha-ketoglutarate levels rescued atrophy in myotubes, and skeletal muscle from cachexia mouse models showed reduced alpha-ketoglutarate, consistent with the same mechanism operating in vivo. The findings define a specific tumour-muscle crosstalk pathway that appears targetable. Whether restoring these metabolites can prevent or reverse cachexia in patients remains untested.
Written by a model from the reports · updated 2 hours ago
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- biorxiv.orgNAD+ limitation and α-ketoglutarate depletion define cancer induced muscle atrophy
Pancreatic cancer cells secrete lactate that lowers the NAD+/NADH ratio in myotubes, impairing oxidative metabolism and depleting alpha-ketoglutarate (KG), which drives muscle atrophy involving cytoskeletal stress and increased myosin contractility. Restoring NAD+ or KG levels rescued myotube atrophy, and skeletal muscle from cachexia mouse models showed reduced KG levels, defining a targetable tumour-muscle crosstalk mechanism.
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