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Histone deacetylase 4/5 (HDAC4/5) are essential for regulating metabolic gene expression; AMPKα2 regulates HDAC4/5 activity and the expression of MuRF1 during exercise. In this study, we used wild-type and AMPKα2-/- mice to explore the potential regulatory relationship between AMPKα2 and HDAC4/5 expression during exercise. Firstly, we fed C57BL/6J mice with high-fat diet for 8 weeks to assess the effects of high-fat diet on skeletal muscle metabolism and HDAC4/5 expression. We then performed a 6-week treadmill exercise on both wild-type and AMPKα2-/- mice. After exercise, the expressions of HDAC4/5 were examined in both gastrocnemius and soleus. The citrate synthase activity and proteins involved in skeletal muscle oxidative process were assessed. To determine the relationship of HDAC4/5 and skeletal muscle oxidative capacity, citrate synthase activity was assessed after silencing HDAC4/5. Moreover, HDAC5 ubiquitination and the association of MuRF1 to HDAC5 were also investigated. Our results showed that 6-week exercise increased the skeletal muscle oxidative capacity and decreased HDAC4/5 expression only in soleus. HDAC5 silencing increased C2C12 cell oxidative capacity. Proteasome inhibition by MG132 abolished exercise-induced HDAC5 degradation mediated by MuRF1-ubiquitin-proteasome system. However, the ubiquitin-proteasome system (UPS) did not dominantly account for exercise-induced HDAC4 degradation. Exercise upregulated MuRF1-HDAC5 association in wild-type mice but not in AMPKα2-/- mice. Our results revealed that 6-week exercise increased the skeletal muscle oxidative capacity and promoted HDAC5 degradation in soleus through the UPS, MuRF1-mediated HDAC5 ubiquitination. Although AMPKα2 played a partial role in regulating MuRF1 expression and HDAC5 ubiquitination, exercise-induced HDAC5 degradation did not fully depend on AMPKα2.

SESN2 and JNK are emerging powerful stress-inducible proteins in regulating lipid metabolism. The aim of this study was to determine the underlying mechanism of SESN2/JNK signaling in exercise to improve lipid disorder induced by high-fat diet (HFD). Our data showed that HFD and SESN2 knockout resulted in abnormalities including elevated body weight, increased fat mass, serum total cholesterol, lipid biosynthesis related proteins, and a concomitant increase of pJNK-Thr183/Tyr185. The above changes were reversed by exercise training. SESN2 silencing or JNK inhibition in palmitate-treated C2C12 further confirmed that SESN2 and JNK play a vital role in lipid biosynthesis. Rescue experiment further demonstrated that SESN2 reduced lipid biosynthesis through inhibition of JNK. SESN2/JNK signaling axis regulates lipid biosynthesis in both animal and cell models with abnormalities of lipid metabolism induced by HFD or palmitate treatment. This study provided evidence that exercise ameliorated lipid metabolic disorder induced by HFD feeding or by SESN2 knockout. SESN2 may improve lipid metabolism through inhibition JNK expression in skeletal muscle cells, providing a molecular mechanism that may represent an attractive target for the treatment of lipid disorder. Novelty: Exercise improved lipid disorder induced by HFD feeding and SESN2 knockout. SESN2 and JNK play a vital role in lipid biosynthesis in vivo and in vitro. SESN2 suppressed JNK to improve lipid metabolism in skeletal muscle cells.

The bone vascular system is important, yet evaluation of bone hemodynamics is difficult and expensive. This study evaluated the utility and reliability of near-infrared spectroscopy (NIRS), a portable and relatively inexpensive device, in measuring tibial hemodynamics and metabolic rate. Eleven participants were tested twice using post-occlusive reactive hyperemia technique with the NIRS probes placed on the tibia and the medial gastrocnemius (MG) muscle. Measurements were made at rest and after 2 levels of plantarflexion exercise. The difference between oxygenated and deoxygenated hemoglobin signal could be reliably measured with small coefficients of variation (CV; range 5.7-9.8%) and high intraclass correlation coefficients (ICC; range 0.73-0.91). Deoxygenated hemoglobin rate of change, a potential marker for bone metabolism, also showed good reliability (CV range 7.5-9.8%, ICC range 0.90-0.93). The tibia was characterized with a much slower metabolic rate compared with MG (p < 0.001). While exercise significantly increased MG metabolic rate in a dose-dependent manner (all p < 0.05), no changes were observed for the tibia after exercise compared with rest (all p > 0.05). NIRS is a suitable tool for monitoring hemodynamics and metabolism in the tibia. However, the local muscle exercise protocol utilized in the current study did not influence bone hemodynamics or metabolic rate. Novelty: NIRS can be used to monitor tibial hemodynamics and metabolism with good reliability. Short-duration local muscle exercise increased metabolic rate in muscle but not in bone. High level of loading and exercise volume may be needed to elicit measurable metabolic changes in bone.

Objective: This study aimed to qualitatively explore perspectives, practices, and barriers to self-care practices (eating habits, physical activity, self-monitoring of blood glucose, and medicine intake behavior) in urban Pakistani adults with type 2 diabetes mellitus (T2DM). Methods: Pakistani adults with T2DM were recruited from the outpatient departments of two hospitals in Lahore. Semistructured interviews were conducted and audiorecorded until thematic saturation was reached. Two researchers thematically analyzed the data independently using NVivo® software with differences resolved by a third researcher. Results: Thirty-two Pakistani adults (aged 35-75 years, 62% female) participated in the study. Six themes were identified from qualitative analysis: role of family and friends, role of doctors and healthcare, patients\' understanding about diabetes, complication of diabetes and other comorbidities, burden of self care, and life circumstances. A variable experience was observed with education and healthcare. Counseling by healthcare providers, family support, and fear of diabetes-associated complications are the key enablers that encourage study participants to adhere to diabetes-related self-care practices. Major barriers to self care are financial constraints, physical limitations, extreme weather conditions, social gatherings, loving food, forgetfulness, needle phobia, and a hectic job. Conclusion: Respondents identified many barriers to diabetes self care, particularly related to life situations and diabetes knowledge. Family support and education by healthcare providers were key influencers to self-care practices among Pakistani people with diabetes.

Accumulation of advanced glycation end products (AGEs) and activation of the receptor for AGEs (RAGE) are implicated in the progression of pathologies associated with aging, chronic inflammation, diabetes, and cellular stress. RAGE activation is also implicated in cardiovascular complications of type 2 diabetes, such as nephropathy, retinopathy, accelerated vascular diseases, and cardiomyopathy. Studies investigating the effects of AGE/RAGE axis activation on skeletal muscle oxidative stress and metabolism are more limited. We tested whether a high-fat diet (HFD) would alter circulating AGE concentration, skeletal muscle AGE accumulation, and oxidative stress in wild-type and RAGE-deficient mice. The physiological significance of AGE/RAGE axis activation in HFD-fed mice was evaluated in terms of exercise tolerance and mitochondrial respiratory chain complex activity. HFD elicited adiposity, abnormal fat distribution, and oral glucose intolerance. HFD also induced accumulation of Nε-carboxymethyl-l-lysine, increased protein carbonyl levels, and impaired respiratory chain complex activity in soleus muscle. Ablation of RAGE had no effects on weight gain and oral glucose tolerance in HFD-fed mice. Peak aerobic capacity and mitochondrial cytochrome-c oxidase activity were restored in HFD-fed RAGE-/- mice. We concluded that RAGE signaling plays an important role in skeletal muscle homeostasis of mice under metabolic stress. Novelty HFD in mice induces accumulation of AGEs, oxidative stress, and mitochondrial dysfunction in the soleus muscle. RAGE, the multi-ligand receptor for AGEs, modulates oxidative stress and mitochondrial electron transport chain function in the soleus muscle of HFD-fed mice.