The Effects of Downhill Running and Maturation on Histological and Morphological Properties of Tendon and Enthesis in Mice

SIMPLE SUMMARY: Tendon and enthesis disorders account for more than half of all sports injuries in adolescents and adults, primarily resulting from overuse. In mice, downhill running is a common intervention to induce overuse. In this study, we examined how changes in the tendons and entheses are induced by different exercise conditions, such as downhill and flat-land running, in mice of different ages, including adolescent and adult mice. We found that downhill running induced hypertrophy of the muscle–tendon complex and enthesis, as well as a significant increase in inflammatory factors in the enthesis, regardless of the age of the mice. In addition, inflammatory factors are expressed in tendons and enthesis due to downhill running at all age group, but the genetic level suggests that the expression change of inflammatory factors were more pronounced in the tendons of adult mice than in the enthesis of adolescent mice. These results will help elucidate the pathogenesis of enthesopathy and tendinopathy, which have different pathophysiologies despite having the same pathogenetic factors. ABSTRACT: To date, it remains unclear how overuse affects the tendons and entheses at different stages of maturation. Therefore, we evaluated histological and morphological changes in the tendons and entheses in adolescent (4-week-old) and adult mice (8-week-old) by performing flat-land and downhill running exercises. The mice were divided into the Sedentary, High Flat (flat-land high-speed running; concentric-contraction exercise), Low Down (downhill low-speed running; eccentric-contraction exercise), and High Down (downhill high-speed running; eccentric-contraction exercise) groups. Histological changes and inflammatory factor expressions were compared in the entheses and tendons after 4 weeks of exercise. Downhill, but not flat-land high-speed running, induced muscle–tendon complex hypertrophy in both adolescent and adult mice. Histological enthesis changes were induced in both groups during downhill running but were less pronounced in adult mice. Conversely, no significant cell aggregation or fiber orientation changes were observed in the tendon, but increased inflammatory factors were observed in both groups, with significantly higher expression in the tendons of adult mice. Downhill running induced histological and morphological enthesis changes and inflammatory factor increase in the tendons, regardless of running speed variations. These results may help elucidate the pathogenesis of enthesopathy and tendinopathy, which have different pathophysiologies despite having the same pathogenetic factors.