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Background: Anti-stress capacity is important to resist the occurrence of adverse events. To observe the effects of exercise, trimetazidine alone or combined on the anti-stress capacity of mice, and further explore its potential mechanism. Methods: Forty-four C57BL/6 male mice aged 8 weeks were randomly divided into four groups (n=11 for each group): control group (group C), exercise group (group E), trimetazidine group (group T), exercise combined with trimetazidine group (group TE). After the intervention, each group was randomly subdivided into the exhaustive exercise (EE, n=6) and the non-EE (n=5) subgroups. The mice in the EE-subgroup underwent EE. Mice were sacrificed 12 hours later after EE. The myocardial ultrastructure and autophagosomes were observed under an electron microscope. The expression of autophagy-related proteins: BNIP3, LC3-II, and P62 were analyzed and the heat shock protein 70 mRNA transcription and protein expression were also investigated. Results: Exercise or trimetazidine increased the expression of BNIP3, LC3-II, and heat shock protein 70, decreased the expression of P62 pre- and post-EE while the combination has the synergistic effect. Conclusion: Exercise and trimetazidine, alone or combined enhanced the anti-stress capacity of mice significantly. The underlying mechanism may be associated with the promotion of autography and the expression of heat shock protein 70.

Mitochondrial quality control (MQC) and function are determinants for cellular energy metabolism, and their disorders are reported to play an important role in the development of insulin resistance (IR). Salidroside was reported to have beneficial effects on MQC through AMPK pathway; however, it is unknown whether salidroside exerts anti-IR effect with this action. This study sought to investigate the effects of salidroside on IR with an exploration of the mechanisms of its action. Experimental IR models were adopted in high-fat-diet (HFD)-fed mice and palmitate-treated C2C12 myotubes, respectively. Blood levels of glucose and insulin as well as cellular glucose uptake were determined, and mitochondrial function and MQC-associated parameters and reactive oxygen species (ROS) production were analyzed based on treatments with the activator (AICAR), inhibitors (compound C and EX-527) or specific siRNA of Ampk/Sirt1 and mitochondrial ROS scavenger (mito-TEMPO). Protein expression level was determined by Western blot, cellular observation by transmission electron microscope and ROS production by functional analysis kits. Salidroside reduced IR and activated insulin signaling along with the stimulation of AMPK/SIRT1 signaling and downstream regulation of MQC and ROS production. These salidroside effects were comparable to those of AICAR and could be prevented by AMPK/SIRT1 inhibitors or siRNAs, respectively. Salidroside reduces IR and regulates MQC and ROS production by activating AMPK/SIRT1 signaling pathway. Since IR is a critical issue for public health, to explore a potent agent against IR is of high interest. The anti-IR effects of salidroside warrant further experimental and clinical studies.

Mounting evidence has firmly established that increased exercise capacity (EC) is associated with considerable improvements in the survival of patients with cardiovascular disease (CVD) and that antistress capacity is a prognostic predictor of adverse cardiovascular events in patients with CVD. Previous studies have indicated that aerobic exercise (AE) and supplementation withRhodiola sacra(RS), a natural plant pharmaceutical, improve EC and enable resistance to stress; however, the underlying mechanism remains unclear. This study explored the ability of AE and RS, alone or combined, to improve EC and ameliorate exhaustive exercise- (EE-) induced stress and elucidate the mechanism involved. We found that AE and RS significantly increased EC in mice and ameliorated EE-induced stress damage in skeletal and cardiac muscles (SCM); furthermore, a synergistic effect was detected for the first time. To our knowledge, the present work is the first to report that AE and RS activate mitophagy, mitochondrial dynamics, and biogenesis in SCM, both in the resting state and after EE. These data indicate that AE and RS synergistically improve EC in mice and protect SCM from EE-induced stress by enhancing mitochondrial quality control, including the activation of mitophagy, mitochondrial dynamics, and biogenesis, both at rest and after EE.

To explore the effects of trimetazidine combined with exercise on EC and anti-fatal stress ability, and illustrate the underlying mechanism.C57BL/6 mice were randomly assigned to four groups (n = 11 in each group): the control, exercise, trimetazidine and trimetazidine + exercise (TE) groups. Mice were accordingly given saline (ig), Aerobic exercise (AE), trimetazidine (ig), or a combination of trimetazidine (ig) and AE for five weeks. After the intervention, each group was randomly subdivided into rest and exhaustive exercise (EE) subgroups. The mice in the control-EE and TE-EE subgroups underwent fatal stress experiments. EC and anti-fatal stress ability were assessed respectively. Mitochondrial quality control (MQC) in skeletal muscle were measured at the protein level and the organelle level.A significantly increased exhaustive swimming time was observed in exercise (39.10 ± 12.58 min vs 14.18 ± 4.37 min), trimetazidine (33.73 ± 8.45 min vs 14.18 ± 4.37 min) and TE groups (73.78 ± 18.95 min vs 14.18 ± 4.37 min) compared with that in the control group, and a synergistic effect was detected (P 0.05). Fatal stress experiments successfully induced skeletal muscle damage, including increased creatine kinase activity, myofibrosis, and impaired antioxidative enzyme system, all those were significantly alleviated by trimetazidine supplementation combined with AE precondition (P 0.05). Meanwhile, AE and trimetazidine alone or combined, significantly enhanced the MQC in normal mice by activating mitochondrial biogenesis, dynamics and mitophagy, and that in mice underwent fatal stress stimulus (P 0.05).This study for the first time found that trimetazidine and AE have synergistic effects on improving EC. Moreover, the combination of both interventions enhances anti-fatal stress ability. Enhancing MQC may be a key mechanism of AE combined with trimetazidine that improves EC and anti-fatal stress ability.

Mounting evidence has firmly established that increased exercise capacity (EC) is associated with considerable improvements in the survival of patients with cardiovascular disease (CVD) and that antistress capacity is a prognostic predictor of adverse cardiovascular events in patients with CVD. Previous studies have indicated that aerobic exercise (AE) and supplementation with Rhodiola sacra (RS), a natural plant pharmaceutical, improve EC and enable resistance to stress; however, the underlying mechanism remains unclear. This study explored the ability of AE and RS, alone or combined, to improve EC and ameliorate exhaustive exercise- (EE-) induced stress and elucidate the mechanism involved. We found that AE and RS significantly increased EC in mice and ameliorated EE-induced stress damage in skeletal and cardiac muscles (SCM); furthermore, a synergistic effect was detected for the first time. To our knowledge, the present work is the first to report that AE and RS activate mitophagy, mitochondrial dynamics, and biogenesis in SCM, both in the resting state and after EE. These data indicate that AE and RS synergistically improve EC in mice and protect SCM from EE-induced stress by enhancing mitochondrial quality control, including the activation of mitophagy, mitochondrial dynamics, and biogenesis, both at rest and after EE.