【Abstract】Objective To explore the potential regulatory mechanism of resistance exercise on senescence accelerated-prone mouse (SAMP8) by comparing the differential expression of lncRNA and mRNA in quadriceps between exercise group and control group by RNA-seq technology. Methods: Twenty-eight-week-old male SAMP8 mice were divided into a model group and resistance exercise group, with six mice in each group. Another eight SAMR1 mice of the same age were used as the control group. The resistance exercise group received 8 weeks of increasing weight climbing exercise training. The relative grip strength was performed every 1 weeks and the rotarod test was performed every 2 weeks. Hematoxylin-eosin staining was used to observe the histological changes of the right quadriceps femoris, and take the left quadriceps for RNA-seq (RNA-sequencing). The differentially expressed long non-coding RNA (lncRNA) and mRNA were screened. These Genes were then analyzed for enrichment by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Finally, the key differentially expressed genes were analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) to verify the accuracy of RNA-seq results. Results: (1) Compared with the control group, the relative grip strength and rotarod test time of model group were decreased significantly(P < 0.01). After 8 weeks of resistance exercise, compared with model group, the relative grasping strength and the rotarod test time of resistance exercise groups were increased significantly(P < 0.01). (2) The results of Hematoxylin-eosin staining showed that compared with the C group, the cross-sectional area of muscle fibers in M group was significantly lower(P < 0.01), compared with the M group, the cross-sectional area of muscle fibers in R group was significantly increased (P < 0.01). (3) Through differential expression analysis, we found 182 upregulated and 218 downregulated lncRNAs, and 454 upregulated and 289 downregulated mRNAs in the comparison between the M group and the R group. The KEGG pathways of lncRNA target genes between the M group and the R group were significantly enriched in Intestinal immune network for IgA production、NF-kappa B signaling pathway、inflammatory bowel disease, etc. Conclusions: (1) This study demonstrated that resistance exercise can improve skeletal muscle function in SAMP8 mice with sarcopenia, and evaluated the differentially expressed lncRNA and mRNA in M group and R group by RNA-seq. These genes may be the target of sarcopenia therapy. (2) By analyzing the biological information of the target genes of differentially expressed lncRNAs and mRNAs, it is possible to further understand the mechanism of resistance exercise to improve sarcopenia.