Voluntary physical activity counteracts Chronic Heart Failure progression affecting both cardiac function and skeletal muscle in the transgenic Tgαq*44 mouse model

Abstract

Physical activity is emerging as an alternative nonpharmaceutical strategy to prevent and treat a variety of cardiovascular diseases due to its cardiac and skeletal muscle beneficial effects. Oxidative stress occurs in skeletal muscle of chronic heart failure (CHF) patients with possible impact on muscle function decline. We determined the effect of voluntary‐free wheel running (VFWR) in preventing protein damage in Tgαq*44 transgenic mice (Tg) characterized by a delayed CHF progression. In the early (6 months) and transition (12 months) phase of CHF, VFWR increased the daily mean distance covered by Tg mice eliminating the difference between Tg and WT present before exercise at 12 months of age (WT Pre‐EX 3.62 ± 1.66 vs. Tg Pre‐EX 1.51 ± 1.09 km, P < 0.005; WT Post‐EX 5.72 ± 3.42 vs. Tg Post‐EX 4.17 ± 1.8 km, P > 0.005). This effect was concomitant with an improvement of in vivo cardiac performance [(Cardiac Index (mL/min/cm 2 ): 6 months, untrained‐Tg 0.167 ± 0.005 vs. trained‐Tg 0.21 ± 0.003, P < 0.005; 12 months, untrained‐Tg 0.1 ± 0.009 vs. trained‐Tg 0.133 ± 0.005, P < 0.005]. Such effects were associated with a skeletal muscle antioxidant response effective in preventing oxidative damage induced by CHF at the transition phase (untrained‐Tg 0.438 ± 0.25 vs. trained‐Tg 0.114 ± 0.010, P < 0.05) and with an increased expression of protein control markers (MuRF‐1, untrained‐Tg 1.12 ± 0.29 vs. trained‐Tg 14.14 ± 3.04, P < 0.0001; Atrogin‐1, untrained‐Tg 0.9 ± 0.38 vs. trained‐Tg 7.79 ± 2.03, P < 0.01; Cathepsin L, untrained‐Tg 0.91 ± 0.27 vs. trained‐Tg 2.14 ± 0.55, P < 0.01). At the end‐stage of CHF (14 months), trained‐Tg mice showed a worsening of physical performance (decrease in daily activity and weekly distance and time of activity) compared to trained age‐matched WT in association with oxidative protein damage of a similar level to that of untrained‐Tg mice (untrained‐Tg 0.62 ± 0.24 vs. trained‐Tg 0.64 ± 0.13, P > 0.05). Prolonged voluntary physical activity performed before the onset of CHF end‐stage, appears to be a useful tool to increase cardiac function and to reduce skeletal muscle oxidative damage counteracting physical activity decline.

Impact of long‐lasting spontaneous physical activity on bone morphogenetic protein 4 in the heart and tibia in murine model of heart failure

“…Hence, an increase in the BMP4 content in heart found in this study, which coincides with activation of the renin–angiotensin pathway (Tyrankiewicz et al, 2018), might be an important factor leading to cardiac remodeling during the disease progression. It has also been demonstrated in our previous papers (Bardi et al, 2019; Grassi et al, 2017), that Tgαq*44 mice, at age between 10 and 12 month (at same age as mice in this study) revealed significantly higher heart hypertrophy index, accompanied by an impaired cardiac function. The latter was characterized with significantly lower stroke volume and ejection fraction when compared with healthy animals (WT mice), at the same age.…”

“…Elevated BMP4 expression in ventricles of the Tgαq*44 mice compared to the control WT mice, observed in our study (Figure 4a), likely results from the RAA system activation. Thus, it may explain higher heart hypertrophy index and impaired cardiac function in Tgαq*44 mice, as presented in our previous papers (Bardi et al, 2019; Grassi et al, 2017).…”

“…In this model of heart failure, the activation of hypertrophic genes and myocardial fibrosis are evident starting from ~4 months of age, cardiac contractile, and mitochondrial functions begin to deteriorate at 8–10 months of age and finally a clinically evident cardiac decompensation usually occurs at ~12–14 months of age, leading to the animals’ death (Czarnowska et al, 2016; Elas et al, 2008; Mackiewicz et al, 2012; Mende et al, 2001). As presented most recently in our papers (Bardi et al, 2019; Grassi et al, 2017), 8‐week voluntary running exercise is potent to delay chronic heart failure progression in Tgαq*44 mice by decreasing hypertrophy index and by improving cardiac function as reflected by an increase in stroke volume and ejection fraction. Considering the role of BMP4 in the pathological cardiac hypertrophy (Sun et al, 2013) our results might suggest that an improvement of cardiac function in chronic heart failure conditions (Bardi et al, 2019; Grassi et al, 2017) might be BMP4‐dependent.…”

“…As presented most recently in our papers (Bardi et al, 2019; Grassi et al, 2017), 8‐week voluntary running exercise is potent to delay chronic heart failure progression in Tgαq*44 mice by decreasing hypertrophy index and by improving cardiac function as reflected by an increase in stroke volume and ejection fraction. Considering the role of BMP4 in the pathological cardiac hypertrophy (Sun et al, 2013) our results might suggest that an improvement of cardiac function in chronic heart failure conditions (Bardi et al, 2019; Grassi et al, 2017) might be BMP4‐dependent. Since an increase in BMP4 expression leads to cardiac hypertrophy and fibrosis through oxidative stress and apoptosis (Sun et al, 2013), a decrease in BMP4 expression in the heart in Tgαq*44 mice after physical training might delay heart failure progression by attenuation of these processes.…”

“…Since an increase in BMP4 expression leads to cardiac hypertrophy and fibrosis through oxidative stress and apoptosis (Sun et al, 2013), a decrease in BMP4 expression in the heart in Tgαq*44 mice after physical training might delay heart failure progression by attenuation of these processes. Interestingly, it has been found that, for example, administration of α‐calcitonin gene‐related peptide delays heart failure progression through the prevention of oxidative stress and apoptosis in the heart of the heart failure mice (Bardi et al, 2019; Kumar, Supowit, Potts, & DiPette, 2019).…”