Objective To explore the potential regulatory mechanism of resistance exercise in senescence accelerated-prone 8 mice ( SAMP8) by evaluating the effects of exercise on the expression of long non-coding RNA (lncRNA) and mRNA in quadriceps muscles by RNA-sequencing (RNA-seq) technology. Methods Twenty-eight-weekold male SAMP8 mice were divided into a model group (M group) and resistance-exercise group (R group) (n = 6 mice per group). Another eight normally aging SAMR1 mice of the same age were used as the control group (C group). Mice in R group received 8 weeks of increasing weight climbing exercise training. Relative grip strength was measured every week and the rotarod test was performed every 2 weeks. Histological changes in the right quadriceps femoris were observed by hematoxylin-eosin staining and the left quadriceps was used for RNA-seq. Differentially expressed lncRNA and mRNA were screened and analyzed for enrichment by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Finally, key differentially expressed genes were analyzed by quantitative reverse transcription-polymerase chain reaction to verify the accuracy of the RNA-seq result. Results ( 1) Relative grip strength and rotarod test time were significantly decreased in M group compared with C group (P< 0. 01), but were significantly increased after 8 weeks of Rgroup compared with M group (P< 0. 01). (2)The cross-sectional area of the muscle fibers was significantly lower in M group compared with C group, as shown by HE staining (P< 0. 01), while the cross-sectional area of the muscle fibers was significantly increased in the R group compared with M group ( P< 0. 01). ( 3) Differential expression analysis identified 182 upregulated and 218 downregulated lncRNA, and 454 upregulated and 289 downregulated mRNA between M group and R group. The KEGG pathways of lncRNA target genes that were differentially expressed between M group and R group were significantly enriched in intestinal immune network for IgA production, nuclear factor-kappa B signaling pathway, and inflammatory bowel disease. Conclusions (1)This study demonstrated that resistance exercise can improve skeletal muscle function in SAMP8 mice with sarcopenia. We identified lncRNA and mRNA that were differentially expressed as a result of resistance exercise, and which might be potential targets of sarcopenia therapy. (2)Furthermore,analyzing the biological functions of the target genes of the differentially expressed lncRNA and mRNA may further our understanding of the mechanism of resistance exercise for improving sarcopenia.