Elucidating cancer cachexia-mediated aberrant cardiac wasting signaling in human iPSC-derived cardiac muscle

作者：Nora Hosny, Houda Cohen, Mohamed Waleed Elafany, Jeff Schreifels, John H. Bauer, Rishi Gulati, Brian R. Thompson, Julia Liu, Joseph M. Metzger · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.08.18.670675 · 被引用次数：2 · 研究领域：Muscle Physiology and Disorders、Nutrition and Health in Aging、Autophagy in Disease and Therapy

Cancer cachexia is a highly debilitating clinical syndrome of involuntary body mass loss featuring profound muscle wasting leading to high mortality. Notably, cardiac wasting is prominent in cancer patients and cancer survivors. Cachexia studies present significant challenges due to the absence of human models and mainly short-term animal studies. To address this translational gap, we have developed a robust human-based cachexia experimental approach characterized by marked cardiac muscle wasting and contractile dysfunction, with increased expression of protein degradation markers. Using human iPSC-derived cardiac muscle, we investigated morphological, functional, and metabolic alterations in the key stages of cachexia and in the post-cachexia phase. C26 and HCT116 tumor cell lines were used to induce cachexia by two methods, pulse addition of cancer cell conditioned media or in transwell-adapted co-culture. Cachectic cardiac myocytes exhibited reduced contraction amplitude, prolonged relaxation time, and increased oxygen consumption rate (OCR), as assessed by video-based and Seahorse analyses. Mechanistic investigations centered on the Atrogin-1/Calcineurin A/NFAT axis revealed this signaling pathway as a central driver of cachexia-induced cardiac atrophy. Cachectic cardiac myocytes exhibited significant upregulation of Atrogin-1, leading to a marked decrease in Calcineurin A protein levels. This, in turn, impaired nuclear translocation of NFAT, thereby suppressing its trans...