Increasing Cardiomyocyte Atrogin-1 Reduces Aging-Associated Fibrosis and Regulates Remodeling in Vivo

Roberto Mota, Traci L. Parry, Cecelia C. Yates, Zhaoyan Qiang, Samuel C. Eaton, Jean Marie Mwiza, Deepthi Tulasi, Jonathan C. Schisler, Cam Patterson, Tania Zaglia, Marco Sandri, Monte S. Willis

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Abstract

The muscle-specific ubiquitin ligase atrogin-1 (MAFbx) has been identified as a critical regulator of pathologic and physiological cardiac hypertrophy; it regulates these processes by ubiquitinating transcription factors [nuclear factor of activated T-cells and forkhead box O (FoxO) 1/3]. However, the role of atrogin-1 in regulating transcription factors in aging has not previously been described. Atrogin-1 cardiomyocyte-specific transgenic (Tg + ) adult mice (α-major histocompatibility complex promoter driven) have normal cardiac function and size. Herein, we demonstrate that 18-month-old atrogin-1 Tg + hearts exhibit significantly increased anterior wall thickness without functional impairment versus wild-type mice. Histologic analysis at 18 months revealed atrogin-1 Tg + mice had significantly less fibrosis and significantly greater nuclei and cardiomyocyte cross-sectional analysis. Furthermore, by real-time quantitative PCR, atrogin-1 Tg + had increased Col 6a4, 6a5, 6a6, matrix metalloproteinase 8 (Mmp8), and Mmp9 mRNA, suggesting a role for atrogin-1 in regulating collagen deposits and MMP-8 and MMP-9. Because atrogin-1 Tg + mice exhibited significantly less collagen deposition and protein levels, enhanced Mmp8 and Mmp9 mRNA may offer one mechanism by which collagen levels are kept in check in the aged atrogin-1 Tg + heart. In addition, atrogin-1 Tg + hearts showed enhanced FoxO1/3 activity. The present study shows a novel link between atrogin-1–mediated regulation of FoxO1/3 activity and reduced collagen deposition and fibrosis in the aged heart. Therefore, targeting FoxO1/3 activity via the muscle-specific atrogin-1 ubiquitin ligase may offer a muscle-specific method to modulate aging-related cardiac fibrosis.

Original languageEnglish (US)
Pages (from-to)1676-1692
Number of pages17
JournalAmerican Journal of Pathology
Volume188
Issue number7
DOIs
StatePublished - Jul 2018

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Mota, R., Parry, T. L., Yates, C. C., Qiang, Z., Eaton, S. C., Mwiza, J. M., Tulasi, D., Schisler, J. C., Patterson, C., Zaglia, T., Sandri, M., & Willis, M. S. (2018). Increasing Cardiomyocyte Atrogin-1 Reduces Aging-Associated Fibrosis and Regulates Remodeling in Vivo. American Journal of Pathology, 188(7), 1676-1692. https://doi.org/10.1016/j.ajpath.2018.04.007