Usage Information
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
Usage data is cumulative from November 2026 through November 2026.
| Usage | JCI | PMC |
|---|---|---|
| Text version | 168 | 0 |
| 46 | 0 | |
| Figure | 81 | 0 |
| Supplemental data | 160 | 0 |
| Citation downloads | 27 | 0 |
| Totals | 482 | 0 |
| Total Views | 482 | |
Usage information is collected from two different sources: this site (JCI) and Pubmed Central (PMC). JCI information (compiled daily) shows human readership based on methods we employ to screen out robotic usage. PMC information (aggregated monthly) is also similarly screened of robotic usage.
Various methods are used to distinguish robotic usage. For example, Google automatically scans articles to add to its search index and identifies itself as robotic; other services might not clearly identify themselves as robotic, or they are new or unknown as robotic. Because this activity can be misinterpreted as human readership, data may be re-processed periodically to reflect an improved understanding of robotic activity. Because of these factors, readers should consider usage information illustrative but subject to change.
