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

Am J Pathol

McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina; Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina; Indiana Center for Musculoskeletal Health and Department of Pathology and Laboratory Medicine, University of Indiana School of Medicine, Indianapolis, Indiana. Electronic address:

Published: July 2018

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.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026801PMC
http://dx.doi.org/10.1016/j.ajpath.2018.04.007DOI Listing

Publication Analysis

Top Keywords

atrogin-1
12
foxo1/3 activity
12
ubiquitin ligase
8
transcription factors
8
role atrogin-1
8
atrogin-1 regulating
8
atrogin-1 tg hearts
8
atrogin-1 tg mice
8
mmp8 mmp9
8
mmp9 mrna
8

Similar Publications

Background: Muscle atrophy after the rupture of a rotator cuff (RC) tendon is a major factor that increases the risk of secondary complications and re-rupture. Metformin, a type 2 diabetes treatment, can be used to modulate intracellular signaling pathways that promote muscle growth. This study aimed to verify whether systemic metformin administration could prevent supraspinatus (SS) atrophy after RC rupture in a rat model.

View Article and Find Full Text PDF

This study aimed to investigate the underlying mechanisms by which physical exercise mitigates muscle atrophy induced by Dexamethasone (Dex). A muscle atrophy model was established in the mouse C2C12 cell line and 8-week-old mice treated with Dex, with subsequent verification of phenotype and atrogene expression. The potential benefits of combined aerobic and resistance exercise in mitigating muscle atrophy were then examined.

View Article and Find Full Text PDF

A and Extract Blend Attenuates Muscle Atrophy by Regulating Protein Metabolism and Antioxidant Activity.

J Med Food

December 2024

Division of Food and Nutrition and Human Ecology Research Institute, Chonnam National University, Gwangju, Republic of Korea.

Here, we investigated whether a mixture of and (1:3, KGC01CE) could suppress muscle atrophy in HO-induced C2C12 cells and dexamethasone-injected mice. Our results revealed that KGC01CE effectively safeguarded against HO-induced muscle atrophy in C2C12 cells compared with the same mixture at other ratios. We demonstrated that dexamethasone elicited oxidative stress in muscle tissue and decreased the grip strength and cross-sectional areas of muscle fibers; however, oral administration of KGC01CE (1:3) suppressed these dexamethasone-induced changes.

View Article and Find Full Text PDF

Fucosterol, a Phytosterol of Marine Algae, Attenuates Immobilization-Induced Skeletal Muscle Atrophy in C57BL/6J Mice.

Mar Drugs

December 2024

Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.

The objective of this study was to examine whether fucosterol, a phytosterol of marine algae, could ameliorate skeletal muscle atrophy in tumor necrosis factor-alpha (TNF-α)-treated C2C12 myotubes and in immobilization-induced C57BL/6J mice. Male C57BL6J mice were immobilized for 1 week to induce skeletal muscle atrophy. Following immobilization, the mice were administrated orally with saline or fucosterol (10 or 30 mg/kg/day) for 1 week.

View Article and Find Full Text PDF

Muscle atrophy, an age-related condition, presents a growing healthcare concern within the context of global population aging. While studies have investigated for its potential antifatigue properties, reports on its active components remain limited. This study evaluated the efficacy of mycelium extract on muscle health, utilizing a 1:1 water-ethanol preparation administered to C57BL/6 mice exhibiting acute hind leg atrophy.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!