Xingran Liu

// Jingjing Fan 1 , Xiaoqi Yang 2 , Jie Li 2 , Ziyang Shu 2 , Jun Dai 2 , Xingran Liu 2 , Biao Li 3 , Shaohui Jia 1 , Xianjuan Kou 1 , Yi Yang 1 and Ning Chen 1 1 Hubei Key Laboratory of Exercise Training and Monitoring, Hubei Provincial Collaborative Innovation Center for Exercise and Health Promotion, College of Health Science, Wuhan Sports University, Wuhan, China 2 Graduate School, Wuhan Sports University, Wuhan, China 3 Graduate School, Jilin Sport University, Changchun, China Correspondence to: Ning Chen, email: // Keywords : D-galactose, spermindine, exercise, autophagy, AMPK-FOXO3a signal pathway, Gerotarget Received : October 26, 2016 Accepted : February 06, 2017 Published : February 25, 2017 Abstract The quality control of skeletal muscle is a continuous requirement throughout the lifetime, although its functions and quality present as a declining trend during aging process. Dysfunctional or deficient autophagy and excessive apoptosis may contribute to the atrophy of senescent skeletal muscle. Spermidine, as a natural polyamine, can be involved in important cellular functions for lifespan extension and stress resistance in several model organisms through activating autophagy. Similarly, cellular autophagic responses to exercise have also been extensively investigated. In the present study, in order to confirm the mitigation or amelioration of skeletal muscle atrophy in aging rats through spermidine coupled with exercise intervention and explore corresponding mechanisms, the rat model with aging-related atrophy of skeletal muscle was established by intraperitoneal injection of D-galactose (D-gal) (200 mg/kg∙d), and model rats were subjected to the intervention with spermidine (5 mg/kg∙d) or swimming (60 min/d, 5 d/wk) or combination for 42 days. Spermidine coupled with exercise could attenuate D-gal-induced aging-related atrophy of skeletal muscle through induced autophagy and reduced apoptosis with characteristics of more autophagosomes, activated mitophagy, enhanced mitochondrial quality, alleviated cell shrinkage, and less swollen mitochondria under transmission scanning microscopic observation. Meanwhile, spermidine coupled with exercise could induce autophagy through activating AMPK-FOXO3a signal pathway with characterization of increased Beclin1 and LC3-II/LC3-I ratio, up-regulated anti-apoptotic Bcl-2, down-regulated pro-apoptotic Bax and caspase-3, as well as activated AMPK and FOXO3a. Therefore, spermidine combined with exercise can execute the prevention or treatment of D-gal-induced aging-related skeletal muscle atrophy through enhanced autophagy and reduced apoptosis mediated by AMPK-FOXO3a signal pathway.

// Xianjuan Kou 1,* , Xingran Liu 2,* , Xianbing Chen 3 , Jie Li 2 , Xiaoqi Yang 2 , Jingjing Fan 1 , Yi Yang 1 and Ning Chen 1 1 Hubei Key Laboratory of Sport Training and Monitoring, College of Health Science, Wuhan Sports University, Wuhan, China 2 Graduate School, Wuhan Sports University, Wuhan, China 3 College of Medicine, Hubei University for Nationalities, Enshi, China * These authors have contributed equally to this work Correspondence to: Ning Chen, email: // Keywords : ampelopsin, aging, autophagy, miR-34a, SIRT1-mTOR signal pathway, Gerotarget Received : July 15, 2016 Accepted : October 17, 2016 Published : October 21, 2016 Abstract The underlying molecular mechanisms for aging-related neurodegenerative diseases such as Alzheimer’s disease (AD) are not fully understood. Currently, growing evidences have revealed that microRNAs (miRNAs) are involved in aging and aging-related diseases. The up-regulation of miR-34a has been reported to be associated with aging-related diseases, and thus it should be a promising therapeutic target. Ampelopsin, also called dihydromyricetin (DHM), a natural flavonoid from Chinese herb Ampelopsis grossedentata , has been reported to possess multiple pharmacological functions including anti-inflammatory, anti-oxidative and anti-cancer functions. Meanwhile, it has also gained tremendous attention against neurodegenerative diseases as an anti-aging compound. In the present study, the model rats with D-gal-induced brain aging revealed an obvious expression of miR-34a; in contrast, it could be significantly suppressed upon DHM treatment. In addition, target genes associated with miR-34a in the presence of DHM treatment were also explored. DHM supplementation inhibited D-gal-induced apoptosis and rescued impaired autophagy of neurons in hippocampus tissue. Moreover, DHM activated autophagy through up-regulated SIRT1 and down-regulated mTOR signal pathways due to the down-regulated miR-34a. In conclusion, DHM can execute the prevention and treatment of D-gal-induced brain aging by miR-34a-mediated SIRT1-mTOR signal pathway.

microRNAs (miRNAs) have been reported to be involved in many neurodegenerative diseases. To explore the regulatory role of miR-34a in aging-related diseases such as Alzheimer’s disease (AD) during exercise intervention, we constructed a rat model with d-galactose (d-gal)-induced oxidative stress and cognitive impairment coupled with dysfunctional autophagy and abnormal mitochondrial dynamics, determined the mitigation of cognitive impairment of d-gal-induced aging rats during swimming intervention, and evaluated miR-34a-mediated functional status of autophagy and abnormal mitochondrial dynamics. Meanwhile, whether the upregulation of miR-34a can lead to dysfunctional autophagy and abnormal mitochondrial dynamics was confirmed in human SH-SY5Y cells with silenced miR-34a by the transfection of a miR-34a inhibitor. Results indicated that swimming intervention could significantly attenuate cognitive impairment, prevent the upregulation of miR-34a, mitigate the dysfunctional autophagy, and inhibit the increase of dynamin-related protein 1 (DRP1) in d-gal-induced aging model rats. In contrast, the miR-34a inhibitor in cell model not only attenuated D-gal-induced the impairment of autophagy but also decreased the expression of DRP1 and mitofusin 2 (MFN2). Therefore, swimming training can delay brain aging of d-gal-induced aging rats through attenuating the impairment of miR-34a-mediated autophagy and abnormal mitochondrial dynamics, and miR-34a could be the novel therapeutic target for aging-related diseases such as AD. NEW & NOTEWORTHY In the present study, we have found that the upregulation of miR-34a is the hallmark of aging or aging-related diseases, which can result in dysfunctional autophagy and abnormal mitochondrial dynamics. In contrast, swimming intervention can delay the aging process by rescuing the impaired functional status of autophagy and abnormal mitochondrial dynamics via the suppression of miR-34a.