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

Am J Pathol. 2018 Jul;188(7):1676-1692. doi: 10.1016/j.ajpath.2018.04.007. Epub 2018 May 23.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging*
  • Animals
  • Cardiomegaly / etiology
  • Cardiomegaly / metabolism
  • Cardiomegaly / prevention & control*
  • Cardiovascular Physiological Phenomena*
  • Cross-Sectional Studies
  • Fibrosis / etiology
  • Fibrosis / metabolism
  • Fibrosis / prevention & control*
  • Mice
  • Mice, Transgenic
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • SKP Cullin F-Box Protein Ligases / genetics
  • SKP Cullin F-Box Protein Ligases / metabolism*
  • Signal Transduction


  • Muscle Proteins
  • Fbxo32 protein, mouse
  • SKP Cullin F-Box Protein Ligases