TREADMILL EXERCISE TRAINING PROTECTS AGAINST METABOLIC DYSFUNCTION AND DIAPHRAGM WEAKNESS IN OBESE DIABETIC RATS
Authors: Ichinoseki‐Sekine Noriko , Tsuzuki Takamasa , Hinkley Matthew J. , Yoshihara Toshinori , Kobayashi Hiroyuki , Powers Scott K. , Naito Hisashi 
Published: June 2021

Excessive weight gain is a serious public health issue, as nearly one‐third of the population worldwide is obese or overweight. Obesity is a major risk factor in the development of various metabolic disorders, including type 2 diabetes. Furthermore, obesity and diabetes results in many physical disabilities, including inspiratory muscle weakness (i.e., diaphragm dysfunction) which can lower the quality of life and increase the risk of respiratory failure. Increased physical activity (i.e., exercise training) has been shown to be a critical intervention to attenuate the metabolic derangements associated with obese diabetics. Furthermore, endurance exercise training alters the diaphragmatic phenotype to protect against various stressors; however, whether endurance exercise training can attenuate obesity/diabetes‐induced diaphragm dysfunction is unclear. Therefore, we investigated the effects of exercise training on obesity/diabetes‐induced diaphragm dysfunction. Male Otsuka Long‐Evans Tokushima Fatty (OLETF) rats, a rodent model of obesity/diabetes, were randomly assigned to either sedentary (SED: n=7) or exercise groups (Ex: n=6). Dependent measures were compared to lean long‐Evans Tokushima Otsuka rats that were sedentary (LETO: n=6). Treadmill running was conducted 5 days/week for 20 weeks from 5 weeks of age for Ex group. An intraperitoneal glucose tolerance test was performed following overnight fasting, and blood and diaphragm samples were obtained 48 h after the final exercise bout. Exercise training positively impacted whole‐body metabolic function of OLETF rats, as indicated by improved glucose tolerance, and reductions in body weight, serum triglyceride, total cholesterol, and insulin that were comparable to LETO rats. A trend (p=0.0511) for decreased blood levels of free fatty acids was also observed in exercise trained OLETF rats. Diaphragm force production in OLETF rats was lower compared to LETO controls, but was rescued by exercise training. Mechanistically, OLETF rats presented increases in myocellular markers associated with diaphragmatic weakness, including increases in angiotensin II type 1 receptor (AT1R) and tumor necrosis factor‐like weak inducer of apoptosis receptor (TWEAKR). Interestingly, in conjunction with improved diaphragm function, the rise in diaphragmatic AT1R and TWEAKR were attenuated by exercise training in OLETF rats. Additionally, increased protein acetylation was prevented in OLETF rats that were exercise trained, potentially due to restoration in the protein abundance of the deacetylase sirtuin 1 (Sirt1) by exercise training (p<0.05). These findings reveal that endurance exercise training protects against metabolic dysfunction and diaphragm weakness observed with obese diabetic rats. These data suggest exercise training is a potential intervention to prevent respiratory muscle weakness associated with obese diabetic individuals.Support or Funding InformationThis work was supported by JSPS KAKENHI 15KK0131 (NIS), MEXT‐Supported Program for the Private University Research Branding Project (HN) and NIH R01, R01AR064189 (SKP)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.