Abstract
Although skeletal muscle is the main effector organ largely accounting for disability after stroke, considerably less attention is paid to the secondary abnormalities of stroke-related skeletal muscle loss. It is necessary to explore the mechanism of muscle atrophy after stroke and further develop effective rehabilitation strategy. Here, we evaluated the effects of high-intensity interval (HIIT) versus moderate-intensity aerobic training (MOD) on physical function, muscle mass, and stroke-related gene expression profile of skeletal muscle. After the model of middle cerebral artery occlusion (MCAO) was successfully made, the blood lactate threshold corresponding speed (SLT) and maximum speed (Smax) were measured. Different intensity training protocols (MOD < SLT; SLT < HIIT < Smax) were carried out for 3 weeks beginning at 7 days after MCAO in the MOD and HIIT groups, respectively. We found that both HIIT and MOD prevented stroke-related gastrocnemius muscle mass loss in MCAO mice. HIIT was more beneficial than MOD for improvements in muscle strength, motor coordination, walking competency, and cardiorespiratory fitness. Furthermore, HIIT was superior to MOD in terms of reducing lipid accumulation, levels of IL-1β and IL-6 in paretic gastrocnemius, and improving peripheral blood CD4+/CD8+ T cell ratio, level of IL-10. Additionally, RNA-seq analysis revealed that the differentially expressed genes among HIIT, MOD, and MCAO groups were highly associated with signaling pathways involved in inflammatory response, more specifically the I-kappaB kinase/NF-kappaB signaling. Following the outcome, we further investigated the infiltrating immune cells abundant in paretic muscles. The results showed that HIIT modulated macrophage activation by downregulating CD86+ (M1 type) macrophages and upregulating CD163+ (M2 type) macrophages via inhibiting the TLR4/MyD88/NFκB signaling pathway and exerting an anti-inflammatory effect in paretic skeletal muscle. It is expected that these data will provide novel insights into the mechanisms and potential targets underlying muscle wasting in stroke.
Highlights
Stroke is one of the leading causes of disability worldwide and imposes a tremendous burden on victims, families, and healthcare systems [1]
The results showed that high-intensity interval training (HIIT) modulated macrophage activation by downregulating CD86+ (M1 type) macrophages and upregulating CD163+ (M2 type) macrophages via inhibiting the TLR4/MyD88/NFκB signaling pathway and exerting an anti-inflammatory effect in paretic skeletal muscle
To determine the change of morphology and function of poststroke skeletal muscle, a cerebral ischemic animal model was established by the middle cerebral artery occlusion (MCAO) method, which significantly caused ~40% ipsilateral brain infarcts in the lateral striatum and cortex regions shown by TTC staining (P < 0:01; Figures 1(c) and 1(d))
Summary
Stroke is one of the leading causes of disability worldwide and imposes a tremendous burden on victims, families, and healthcare systems [1]. The skeletal muscle is the main effector organ largely accounting for disability in stroke patients, most of the researches on motor dysfunction after stroke focus on the concept of neurovascular unit throughout the last two decades [3, 4]. Less attention is paid to the secondary abnormalities of stroke-related skeletal muscle loss or sarcopenia. Sarcopenia is defined as “progressive and comprehensive syndrome of skeletal muscle loss and strength decline” with increased risk of adverse consequences including higher mortality, quality of life decline, increased rate of falls, and fractures [5]. Sarcopenia is divided into primary sarcopenia caused by aging, and secondary sarcopenia which is activity-related, nutrition-related, or disease-related [6]. Strokerelated sarcopenia is independent of age, showing a rapid muscle mass loss, and significantly bilateral differences in Mediators of Inflammation physical and functional performance [7]. The most widely recognized etiologic factors include denervation, insulin resistance, poor nutritional status, physical inactivity, and inflammation [8]
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