Fu, Siqian

ABSTRACT Background The optimal exercise regimen for alleviating sarcopenia remains uncertain. This study aimed to investigate the efficacy of high‐intensity interval training (HIIT) over moderate‐intensity continuous training (MICT) in ameliorating sarcopenia. Methods We conducted a randomized crossover trial to evaluate plasma proteomic reactions to acute HIIT (four 4‐min high‐intensity intervals at 70% maximal capacity alternating with 4 min at 30%) versus MICT (constant 50% maximal capacity) in inactive adults. We explored the relationship between a HIIT‐specific protein relative to MICT, identified via comparative proteomic analysis, eukaryotic translation elongation factor 1 epsilon 1 (EEF1E1) and sarcopenia in a paired case–control study of elderly individuals (aged over 65). Young (3 months old) and aged (20 months old) mice were randomized to sedentary, HIIT and MICT groups (five sessions/week for 4 weeks; n = 8 for each group). Measurements included skeletal muscle index, hand grip strength, expression of atrophic markers Atrogin1 and MuRF1 and differentiation markers MyoD, myogenin and MyHC‐II via western blotting. We examined the impact of EEF1E1 siRNA and recombinant protein on D‐galactose‐induced myoblast senescence, measuring senescence‐associated β‐galactosidase and markers like p21 and p53. Results The crossover trial, including 10 sedentary adults (32 years old, IQR 31–32) demonstrated significant alterations in the abundance of 21 plasma proteins after HIIT compared with MICT. In the paired case–control study of 84 older adults (84 years old, IQR 69–81; 52% female), EEF1E1 was significantly increased in those with sarcopenia compared to those without (14.68 [95%CI, 2.02–27.34] pg/mL, p = 0.03) and was associated with skeletal muscle index ( R 2 = 0.51, p < 0.001) and hand grip strength ( R 2 = 0.54, p < 0.001). In the preclinical study, aged mice exhibited higher EEF1E1 mRNA and protein levels in skeletal muscle compared to young mice, accompanied by a lower muscle mass and strength, increased cellular senescence and protein degradation markers and reduced muscle differentiation efficiency (all p < 0.05). HIIT reduced EEF1E1 expression and mitigated age‐related muscle decline and atrophy in aged mice more effectively than MICT. Notably, EEF1E1 downregulation via siRNA significantly counteracted D‐galactose‐induced myoblast senescence as evidenced by reduced markers of muscle protein degradation and improved muscle differentiation efficiency (all p < 0.05). Conversely, treatments that increased EEF1E1 levels accelerated the senescence process ( p < 0.05). Further exploration indicated that the decrease in EEF1E1 was associated with increased SIRT1 level and enhanced autophagy. Conclusions This study highlights the potential of HIIT as a promising approach to prevent and treat sarcopenia while also highlighting EEF1E1 as a potential intervention target.

Background: The role of minute ventilation/carbon dioxide production ( / CO2) slope, a ventilation efficiency marker, in predicting short-term and long-term health outcomes for patients with nonsmall-cell lung cancer (NSCLC) undergoing lung resection has not been well investigated. Material and Methods: This prospective cohort study consecutively enrolled NSCLC patients who underwent a presurgical cardiopulmonary exercise test from November 2014 to December 2019. The association of / CO2 slope with relapse-free survival (RFS), overall survival (OS), and perioperative mortality was evaluated using the Cox proportional hazards and logistic models. Covariates were adjusted using propensity score overlap weighting. The optimal cut-off point of the E/ CO2 slope was estimated using the receiver operating characteristics curve. Internal validation was completed through bootstrap resampling. Results: A cohort of 895 patients [median age (interquartile range), 59 (13) years; 62.5% male] was followed for a median of 40 (range, 1–85) months. Throughout the study, there were 247 relapses or deaths and 156 perioperative complications. The incidence rates per 1000 person-years for relapses or deaths were 108.8 and 79.6 among patients with high and low E/ CO2 slopes, respectively [weighted incidence rate difference per 1000 person-years, 29.21 (95% CI, 7.30–51.12)]. A E/ CO2 slope of greater than or equal to 31 was associated with shorter RFS [hazard ratio for relapse or death, 1.38 (95% CI, 1.02–1.88), P=0.04] and poorer OS [hazard ratio for death, 1.69 (1.15–2.48), P=0.02] compared to a lower / CO2 slope. A high E/ CO2 slope increased the risk of perioperative morbidity compared with a low E/ CO2 slope [odds ratio, 2.32 (1.54–3.49), P<0.001]. Conclusions: In patients with operable NSCLC, a high E/ CO2 slope was significantly associated with elevated risks of poorer RFS, OS, and perioperative morbidity.

Introduction Insulin resistance (IR) plays a key role in the pathogenesis and clinical course of patients with multiple metabolic diseases and diabetes. This study aimed to explore the effect of trimetazidine (TMZ) on skeletal muscle IR in mice fed a high-fat diet (HFD) and explore the possible underlying mechanism. Research design and methods In vivo, a HFD mouse IR model was adopted and TMZ and exercise were used to intervene. Postintervention the following were determined: blood levels of glucose and insulin, homeostasis model assessment of IR index, expression of skeletal muscle insulin signaling-related proteins phosphorylated insulin receptor substrate 1 (p-IRS1/IRS1) and phosphorylated protein kinase B (p-AKT/AKT), nuclear factor erythroid 2 related factor 2 (Nrf2) signaling pathway, and oxidative stress. In vitro, a palmitate-treated C2C12 myotube IR model was constructed. Cellular glucose uptake, p-IRS1/IRS1, and p-AKT/AKT were determined, and reactive oxygen species (ROS) production was analyzed based on treatments with specific small interfering RNA of Nrf2 with or without TMZ. Western blot was used to obtain the protein expression level and ROS production by functional analysis kits. Results In vivo, TMZ and exercise decreased the blood glucose and insulin levels and homeostasis model assessment of IR index, increased skeletal muscle insulin signaling-related protein ratios of p-IRS1/IRS1 and p-AKT/AKT, and both interventions activated Nrf2 signaling and reduced oxidative stress production in HFD mice. In vitro, TMZ reduced the oxidative stress reaction, increased the ratios of p-AKT/AKT and p-IRS1/IRS1, and attenuated the insulin stimulation of PA-induced glucose uptake. However, in the absence of Nrf2, TMZ failed to resist the effects of IR. Conclusions This study showed that TMZ, like exercise, brought about marked improvements to HFD-induced skeletal muscle IR through TMZ, a common pathway with exercise in the form of Nrf2, regulating oxidative stress. We provide new evidence to support the use of TMZ for diabetes treatment.