Exercise Training Preserves Myocardial Strain and Improves Exercise Tolerance in Doxorubicin-Induced Cardiotoxicity

Figure 1. Experimental design. Doxorubicin was administered weekly (5 mg/kg i.p. for 5-wk), concomitantly with low-to-moderate intensity aerobic exercise training (40–50% maximal exercise capacity for 40 min, 4 days per week), or follow-up. Co, control (n = 12); Doxo, doxorubicin (n = 20); Doxo + ExTr, doxorubicin + exercise training (n = 20); ExTr, exercise training.

Figure 2. Exercise training alleviates Doxo-induced cardiac dysfunction. Doxo impairs CO (A) and LVEF (B). However, speckle tracking showed ExTr preserved SAX cardiac contractility, both in the Circ strain (C,D) and strain rate (E,F), expressed as a final vector from strain (B) and strain rate (D) of different cardiac segments (D,F). AFW, anterior free wall; AS, anterior septum; CO, cardiac output; Circ, circumferential; IFW, inferior free wall; LW, lateral wall; LVEF, left ventricular ejection fraction; PS, posterior septum; PW, posterior wall; SAX, short axis). Conceptual analysis of speckle tracking on (G). n = 6–11 per group. Group abbreviations as in Figure 1. *P ≤ 0.05.

Figure 3. ExTr alleviates Doxo-induced cardiopulmonary atrophy. Doxo induces cardiac (A), left ventricle (B), and lung (C) mass atrophy (normalized by tibia length and expressed in mg/mm), which is alleviated by ExTr. Fulton's index (RV/LV + S) reduces with Doxo and is partially preserved by ExTr (D). ExTr prevents cardiomyocyte atrophy induced by Doxo (E). Doxo increases cardiac collagen deposition that is not prevented by ExTr (F). Group abbreviations as in Figure 1. N = 8–11 (A–D), >500 cardiomyocytes pooled from n = 2–3 (E) and n = 5 (F) per group. *P ≤ 0.05.

Figure 4. Molecular markers of Doxo-induced cardiotoxicity. Cardiac protein expression of GATA4 analyzed by densitometry and normalized against β-actin (A) and its nuclear/cytosol ratio (B); the ratio of pERK-to-total-ERK (C) and representative blots (D); protein levels of the antioxidant enzyme superoxide dismutase isoforms 1 (E), 2 (F), or 3 (G) and its representative blots (H). GATA4, GATA binding protein 4; ERK, extracellular signal-regulated kinases; pERK, phosphorylated ERK; SOD, superoxide dismutase. Group abbreviations as in Figure 1. n = 5–8 per group. *P ≤ 0.05.

Figure 5. ExTr exacerbates Doxo-induced body wasting. Doxo induces body wasting, which is exacerbated by ExTr (A), although without negatively affecting survival (B). Doxo affects fat depots mass, reducing both BAT (C) and WAT (D) adipose tissue. ExTr attenuates BAT mass wasting, but not WAT. No changes were found in skeletal muscle mass (E). BAT, brown adipose tissue; WAT, white adipose tissue. Group abbreviations as in Figure 1. n = 12–20 per group (A,B) or n = 8–10 (C–E). *P ≤ 0.05.

Figure 6. ExTr blunts Doxo-induced effort intolerance. Effort tolerance, determined maximal running capacity, shows Doxo total running time from Baseline trend to impair (A), and running performance (B) and total running time (C) were reduced. Interestingly, the better the cardiac contractility (strain rate), the higher is exercise capacity (D) among Doxo-treated groups. J, joule; SAX, short axis. Group abbreviations as in Figure 1. n = 10–12 per group. *P ≤ 0.05.