AICAR Treatment Does Not Prevent Increases in Exercise Capacity or Muscle Heat Shock Protein 25 with Treadmill Training in Mice

Abstract

Exercise and 5‐aminoimidazole‐4‐carboxamide‐1‐β‐D‐ribofuranoside (AICAR) are agonists of AMP‐activated protein kinase (AMPK) and are used in type II diabetes treatment. Treatment effectiveness may be due to AMPK activation and up‐regulation of heat shock proteins (Hsps) in skeletal muscle, including Hsp25 and αB‐crystallin. Decreased Hsp25 expression in skeletal muscle is associated with insulin resistance in rats and data in both animals and humans suggests that increased Hsp expression in skeletal muscle may contribute to the prevention and treatment of insulin resistance. However, some evidence in both animals and humans suggests the combination of exercise and AMPK‐activating drugs such as AICAR may decrease exercise‐training adaptations. These experiments tested the hypothesis that AICAR + treadmill training (TM) would attenuate increases in exercise capacity, muscle force, and Hsp expression compared to training alone. Adult, male C57 mice were divided into 4 groups (n = 8–10/group): 1‐Placebo, 2‐AICAR, 3‐Placebo + TM, and 4‐Aicar + TM. Groups received daily placebo or AICAR with or without TM over 7 days. Plantarflexor muscle force and fatigue (% of max force after 10 contractions) were measured in vivo and exercise capacity was assessed with pre‐ and post‐treadmill tests. Muscle Hsp25 and αB‐crystallin protein levels were quantified with western blot. Data was statistically analyzed with 2‐way ANOVAs and post‐hoc tests. AICAR + TM did not affect training‐associated increases in exercise capacity compared to Placebo + TM (D time pre to post: 903 ± 164 vs. 1,188 ± 99 sec. for AICAR and TM, respectively, p<0.05). Muscle force was unchanged with AICAR in either TM or sedentary groups compared to placebo (Placebo: 1.2 ± 0.07 vs. 1.3± 0.07 and AICAR: 1.4 ± 0.08 vs. 1.5 ± 0.12 g/g body mass, for sedentary and TM, respectively, p<0.05). Fatigability was greater with AICAR in sedentary mice; however, AICAR + TM decreased fatigability compared to AICAR alone (p<0.05). TM increased Hsp25 levels independent of treatment (Placebo: 0.09 ± 0.01 vs. 0.15 ± 0.01 and AICAR 0.15 ± 0.02 vs. 0.17 ±0.02 AU, for sedentary and TM, respectively, p<0.05) and AICAR increased Hsp25 in the sedentary group compared to placebo (0.15 ± 0.02 vs. 0.09 ± 0.01 AU, p<0.05). AICAR prevented the TM‐associated increase in αB‐crystallin compared to placebo (Placebo: 0.11 ± 0.02 vs. 0.17 ± 0.01 and AICAR: 0.10 ± 0.01 vs. 0.01 ± 0.02 AU, for sedentary and TM, respectively, p<0.05). These findings suggest AICAR does not impair training‐associated increases in exercise capacity or Hsp25 muscle protein or negatively impact muscle force production. Taken together, these treatments could positively impact type II diabetics who often have reduced exercise capacity and skeletal muscle Hsp25 levels.Support or Funding InformationSupported by APS UGSRF.