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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 ( S LT ) and maximum speed ( S max ) were measured. Different intensity training protocols (MOD < S LT ; S LT < HIIT < S max ) 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. [ABSTRACT FROM AUTHOR]