Life-Long Aerobic Exercise Alleviates Sarcopenia Through Regulating The Functional Status Of Autophagy

Objective:Sarcopenia is an aging syndrome characterized by the progressive reduction in the mass and strength of skeletal muscle.Recently,increasing evidences indicate that the functional status of autophagy plays an essential role in the progression and treatment of sarcopenia due to its impact on the stability of internal milieu and physiological functions of skeletal muscle cells.Appropriate exercise can induce autophagy or regulate the functional status of autophagy.Additionally,exercise-induced autophagy is the one of the most effective treatment strategies available in slowing down sarcopenia.As a healthy lifestyle,regular lifelong exercise is not only beneficial to health,but also helpful for delaying senescence.Therefore,this study aimed to explore the mechanisms for the prevention,rehabilitation and treatments of sarcopenia through life-long aerobic exercise intervention based on the regulation of autophagic signal pathways,and to clarify the crucial role of autophagy in the process of sarcopenia,which will provide effective theoretical references for promoting a safe and appropriate concept of life-long exercise.Methods: Three-month-old ICR mice were used to construct a mouse model with sarcopenia by natural feeding and exercise intervention for 55 weeks to 17 months.Twenty mice were randomly divided into two groups including the control group(OC)and the life-long aerobic exercise group(OE),with 10 mice in each group.Another 10 three-month-old ICR mice were directly purchased as the youth control group(YC)after the natural aging model was successfully constructed.The experimental animals were subjected to moderate-intensity aerobic exercise for 55 weeks.After the modeling,the body weight was measured,and all mice were sacrificed by cervical dislocation.The gastrocnemius muscle of the left and right hind limbs of the mice was collected respectively.The gastrocnemius muscle weight was measured to calculate the ratio between gastrocnemius muscle and body weight as the evaluation index of the muscle atrophy rate.HE staining was used to observe the morphological changes of skeletal muscle and the cross-sectional area of muscle fibers.The expression of the proteins involved in autophagy,apoptosis,mitochondrial quality control and protein degradation were determined by Western blot.Results:1.The gastrocnemius muscle/body weight ratio: compared with the YC group,the mice from OC group revealed the significantly decreased gastrocnemius muscle/body weight ratio and obvious atrophy symptoms of skeletal muscle(p < 0.001).However,compared with the OC group,the gastrocnemius muscle/body weight ratio of the mice in the OE group was significantly increased,indicating that lifelong aerobic exercise could effectively delay the decline of skeletal muscle mass(p < 0.01);2.Morphological changes: HE staining: compared with YC group,the gastrocnemius muscle in the mice from OC group revealed more atrophic cells,as manifested by decreased fiber cross-section of skeletal muscle and increased number of migrated nuclei.However,after life-long aerobic exercise intervention,the number of atrophic cells and migrated nuclei was decreased,and the cross-section area of muscle fibers in mice from the OE group revealed an obvious increase.3.Western blot results: compared with the YC group,The expression of autophagy-related Beclin1 and LC3-II/LC3-I ratio in skeletal muscle of the mice from OC group decreased significantly(p < 0.01),while the expression level of p62 increased(p < 0.01);the expression of apoptosis-related protein such as Bax and Cleaved-Caspase-3 increased significantly(p < 0.001),and the expression level of Bcl-2 decreased significantly(p < 0.01);the expression of mitophagy related proteins such as Parkin and PINK were significantly decreased(p < 0.01),and the expression of mitochondrial kinetics related proteins including Mfn2 and Drp1 was significantly decreased(p < 0.01,p < 0.001).The expression levels of FoxO3 a,atrogin-1 and MuRF1 associated with ubiquitin-protease system were significantly increased(p < 0.001,p < 0.01,p < 0.001).Compared with the OC group,the expression of Beclin1 and LC3-II/LC3-I ratio associated with of autophagy in skeletal muscle of the mice from the OE group increased significantly(p < 0.001);in contrast,p62 expression level decreased(p < 0.001).The expression of apoptosis-related proteins such as Bax and Cleaved-Caspase-3 decreased significantly(p < 0.001),and the expression level of Bcl-2 increased significantly(p < 0.01).The expression of Parkin and PINK increased significantly(p < 0.01),and the expression of Mfn2 and Drp1 increased significantly(p < 0.01).The expressions of FoxO3 a,atrogin-1 and MuRF1 increased significantly(p < 0.001,p < 0.5,p < 0.001).Conclusion: Life-long aerobic exercise can effectively activate autophagy of skeletal muscle cells,suppress apoptosis,regulate the dynamic balance between fusion and fission of mitochondria,optimize the quality of mitochondria,reduce the excessive activation of ubiquitin-protease system,thereby alleviating protein degradation of skeletal muscle,and preventing and delaying sarcopenia.