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Abstract
Cancer cachexia is a debilitating syndrome of involuntary body mass loss featuring profound skeletal muscle wasting and high mortality. Cardiac muscle wasting is prominent in cancer patients and cancer survivors. We developed a human induced pluripotent stem cell–derived cardiac myocyte (hiPSC-CM) platform modeling cancer cachexia using conditioned media and Transwell coculture with C26 or HCT116 tumor cells. Cachectic hiPSC-CMs exhibited atrophy, reduced contraction amplitude, prolonged relaxation time, and elevated oxygen consumption rate, reflecting wasting, contractile dysfunction, and metabolic dysregulation. Mechanistically, suppression of the AKT/mTORC1/S6 signaling axis notably reduced total and p-AKT, decreased the p-S6/S6 ratio, and downregulated RPTOR, which coincided with FOXO1/3 activation and FOXO1 nuclear translocation, promoting downstream atrophic remodeling. Concurrently, Atrogin-1 upregulation reduced calcineurin A, impairing NFAT nuclear translocation, thereby suppressing downstream growth signaling. Increased autophagic flux with an elevated LC3BII/LC3BI ratio accompanied these changes. Following withdrawal of cachexia-inducing stimuli, Atrogin-1 and autophagy markers normalized within 1 week; however, contractile and metabolic impairments persisted, indicating delayed functional recovery. These findings establish the FOXO/Atrogin-1/calcineurin A/NFAT axis, operating within the broader context of AKT/mTORC1 suppression, as a central regulatory mechanism of cachexia-induced cardiac wasting, unveiling a tractable therapeutic target.
Authors
Nora Hosny, Houda Cohen, Mohamed Waleed Elafany, Jeff Schreifels, John Bauer, Rishi Gulati, Brian R. Thompson, Julia C. Liu, Joseph M. Metzger
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