Exercise-induced Fatigue is Mediated by Muscarinic Cholinoceptors within the Ventromedial Hypothalamus

PURPOSE: Muscarinic blockade of the ventromedial hypothalamic nucleus (VMH) inhibited the activation of cutaneous heat loss mechanisms, increasing exercise-induced hyperthermia and leading to a 37% decrease in performance at an ambient temperature of 23°C. Therefore, we investigate the role of muscarinic cholinoreceptors within the VMH on fatigue development and on thermoregulatory adjustments during exercise in cold environments, when cutaneous heat loss is inhibited. METHODS: Rats were familiarized to run on a motor-driven treadmill for small animals across five consecutive days. The animals were then anesthetized with pentobarbital sodium (50 mg/kg body weight i.p.) and fitted with bilateral cannulae into the VMH one week prior to the experiments. The rats were randomly assigned to receive bilateral injections of 0.2 μL of 5×10−9 mol methylatropine (Matr) or 0.15 M NaCl solution (Sal) into the VMH. Immediately after the injections, rats were placed inside the environmental chamber and were submitted to exercise on a treadmill that consisted of running at 20 m.min−1 and 5% inclination until the point of fatigue. Each animal was submitted to two experimental trials, in one of the following ambient temperature 5, 12 or 15°C. Tail skin (Ttail) and core body temperatures (Tcore) were measured throughout the experiments. RESULTS: Muscarinic blockade of the VMH reduced running time to fatigue by 37% at 5°C (53.7 ± 6.7 min, Sal vs. 33.6 ± 4.6 min, Matr; p < 0.001), 36% at 12°C, (49.3 ± 3.8, Sal vs. 31.5 ± 2.8 min, Matr; p = 0.001) and 35% at 15°C (50.7 ± 4.7, Sal vs. 35.1 ± 3.6 min, Matr; p = 0.002). In saline-treated rats, Tcore reduced during exercise at 5°C, increased at 15°C and was not changed at 12°C. Ttail decreased as soon as exercise had started and remained lower until the point of fatigue, at the ambient temperatures of 5, 12 or 15°C. Bilateral injections of methylatropine into the VMH did not alter Tcore and Ttail compared to saline trial in all three ambient temperatures studied. CONCLUSIONS: Our results indicate that below the zone of thermoneutrality, the blockade of muscarinic cholinoceptors within the VMH decreased the duration of exercise until fatigue independent from changes in Tcore. These data indicate that muscarinic transmission within the VMH modulates performance even when the contribution of thermoregulatory responses to fatigue is minimal.