NAD+ limitation and α-ketoglutarate depletion define cancer induced muscle atrophy
- 1The Francis Crick Insitute
Abstract
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.
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BibTeX
@misc{papalazarou2026limitation,
title = {{NAD+ limitation and α-ketoglutarate depletion define cancer induced muscle atrophy}},
author = {V. Papalazarou and J. Coomes and L. Rossi and V. M. Lionello and I. Furlani and F. S. Tedesco and K. Vousden},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.15.759464},
url = {https://www.biorxiv.org/content/10.64898/2026.10.15.759464v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - NAD+ limitation and α-ketoglutarate depletion define cancer induced muscle atrophy
AU - V. Papalazarou
AU - J. Coomes
AU - L. Rossi
AU - V. M. Lionello
AU - I. Furlani
AU - F. S. Tedesco
AU - K. Vousden
PY - 2026
DA - 2026/10/15
PB - bioRxiv
DO - 10.64898/2026.10.15.759464
UR - https://www.biorxiv.org/content/10.64898/2026.10.15.759464v1
AB - 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.
ER -