Aging, exercise, and extracellular matrix in the heart

Abstract

Aging is characterized by a progressive impairment of (a) cardiac structure including fibrosis and cardiomyocyte density, and (b) cardiac function including stroke volume, ejection fraction, and cardiac output. The cardiac remodeling involves loss of cardiac myocytes, reactive hypertrophy of the remaining cells, and increased extracellular matrix (ECM) and fibrosis in the aging heart, especially left ventricles. Fibrosis (i.e., accumulation of collagen) with aging is very critical in impairing cardiac function associated with increased myocardial stiffness. The balance of ECM remodeling via ECM synthesis and degradation is essential for normal cardiac structure and function. Thus an understanding of upstream ECM regulatory factors such as matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), and myofibroblasts is necessary for gaining new insights into managing cardiac remodeling and dysfunction with aging. In contrast, exercise training effectively improves cardiac function in both young and older individuals. Exercise training also improves maximal cardiovascular function by increasing stroke volume and cardiac output. However, limited data indicate that exercise training might attenuate collagen content and remodeling in the aging heart. We recently found that 12 weeks of exercise training protected against geometric changes of collagen ECM in the aging heart and ameliorated age-associated dysregulation of ECM in the heart, as indicated by up-regulation of active MMPs as well as down-regulation of TIMPs and TGF-β. This review will provide a summary and discussion of aging and exercise effects on fibrosis and upstream regulators of ECM in the heart.

Keywords: Aging; Collagen; Exercise; Extracellular matrix; Heart.

Fig. 1.

Collagen ECM turnover signaling in the heart. Altered mechanical stress (σ) and oxidative stress may stimulate TNF-α, TGF-β, and MMP. TNF-α may stimulate MMP and inhibit TIMP. However, TGF-β may inhibit MMP and stimulate TIMP and myofibroblast. Finally, MMP degrades collagens, but TIMP and myofibroblast inhibit collagen degradation and promote collagen synthesis, which determine collagen ECM remodeling.

Fig. 2.

Effects of aging and exercise training on TIMP-1 and TGF-β1 in the heart. (A) TIMP-1 protein levels and (B) TGF-β1 protein levels of left ventricles in young sedentary (YS), young exercise (YE), old sedentary (OS), and old exercise (OE) groups (Kwak et al., 2011).