The impact of moderate and high intensity endurance exercise on acute murine coxsackievirus B3 myocarditis

Abstract

Background and aims

Myocarditis is a group of inflammatory diseases of the myocardium, with viral infections being the leading cause. Previous murine studies have demonstrated a detrimental effect of extensive exercise on the acute course of viral myocarditis. Recently, we were the first to report that continuation of moderate exercise during murine viral myocarditis modulates myocardial inflammation and fibrosis at the late stage of disease, yet we did not evaluate early time points. In this study, we aimed to evaluate the impact of moderate intensity training on the acute course of disease, and compare it to the effects of a high intensity protocol.

Methods and results

Two separate experiments were performed. For the moderate intensity (Mod) endurance exercise experiment, 50 male C57BL/6J mice (11 weeks old) were randomised to 3 weeks of treadmill running (ModEEX, 18 cm/sec, daily) or not (ModSED). Two weeks into the experiment, animals received a single intraperitoneal injection with either coxsackievirus B3 (CVB) to induce viral myocarditis, or phosphate-buffered saline (PBS) vehicle. For the high intensity (Hi) endurance exercise experiment, another 20 male C57BL/6J mice (17 weeks old) were randomised to 3 weeks of treadmill running (HiEEX) or not (HiSED). After two weeks of training, all animals of the Hi experiment were injected with CVB, and the training protocol was intensified with increasing running speeds until exhaustion in the final week of training. All animals were sacrificed 6-7 days after virus or vehicle administration. All groups demonstrated complete survival except for 1 animal of the HiSED group, and showed comparable clinical signs and body weight evolution. Nor moderate, neither high intensity exercise had any significant impact on plasma troponin levels, semiquantitative scores of cardiomyocyte loss, and digital areas of necrosis. Morphologically however, HiEEX mice showed markedly less inflammatory cells in the necrotic areas of the myocardial lesions compared to HiSED mice, as was confirmed by digital quantification (x10³ inflammatory cells per mm² HiEEX: 6.24±0.32SEM vs HiSED: 8.02 ±0.36SEM, P=0.002). The same digital quantification did not show significant differences between ModEEX and ModSED lesions. Using an extensive panel of immunohistochemical inflammatory cell markers, a different composition of inflammatory cell subtypes was observed in the myocardial lesions of HiEEX compared to ModEEX mice, with a shift towards a pro-inflammatory milieu in HiEEX mice (ratio iNOS/Arg1 HiEEX: 0.49 vs ModEEX: 0.22, P=0.041 and ratio Tbet/GATA3 HiEEX: 4.75 vs ModEEX: 0.82, P=0.005). The cardiac viral load varied considerably, but no impact of exercise was observed, nor did cardiac expression of remodelling genes (Serpina3n, CTGF, and TGF-β) show an exercise effect.

Conclusion

In the acute phase of murine viral myocarditis, lesions show significantly fewer inflammatory cells in the myocardial lesions when performing high intensity exercise during infection. Moreover, compared to moderate intensity exercise, the composition of the inflammatory infiltrate shifts towards a more pro-inflammatory phenotype.