Fatigue during high-intensity endurance exercise: the interaction between metabolic factors and thermal stress.

The purpose of this study was to examine the effects of hot (37° C) and cool (10° C) environments on cycling time to exhaustion (TTE), pH, lactate, and core temperature (Tc). Eleven endurance-trained subjects completed 4 TTE trials: Hot 80% VO2max (H80), Cool 80% (C80), Hot 100% (H100), and Cool 100% VO2max (C100). Esophageal temperature and blood was sampled before, every 5 minutes, at exhaustion, and 3 minutes after exercise and analyzed for lactate, pH, and HCO3-. Multifactorial analysis of variance with repeated measures was used to determine differences between mean values (± SD). Time to exhaustion was shorter in H100 and C100 vs. H80 and C80 (5.64 ± 1.49 minutes, 5.83 ± 1.03 minutes, 12.82 ± 2.0 minutes, and 24.85 ± 6.0 minutes, respectively) and shorter in H80 vs. C80 (p < 0.01). The pH at exhaustion was different among all conditions (7.17 ± 0.06, 7.15 ± 0.07, 7.21 ± 0.04, and 7.24 ± 0.06 units for H100, C100, H80, and C80, respectively, p = 0.02). The Tc at exhaustion was lower in H100 and C100 (37.93 ± 0.67 and 37.62 ± 0.58° C) vs. H80 and C80 (38.54 ± 0.51° C and 38.53 ± 0.38° C) (p < 0.01). In H80 and C80, the higher Tc likely played a greater role in the termination of exercise, whereas, in H100 and C100, pH and metabolic changes may have been more important. Despite these differences, neither an upper limit for Tc nor a lower limit for pH was identified; thus, fatigue based entirely on peripheral factors was not supported, and a combination of peripheral and central processes must be considered. The practical implications of these findings are that aerobic exercise at or near VO2max may be impacted more by metabolic factors, whereas lower intensities (∼80% VO2max) may be affected more by heat stress; these differences should be considered when training for events of this type.

Autoregulatory control of microtubule binding in doublecortin-like kinase 1.

The microtubule-associated protein, doublecortin-like kinase 1 (DCLK1), is highly expressed in a range of cancers and is a prominent therapeutic target for kinase inhibitors. The physiological roles of DCLK1 kinase activity and how it is regulated remain elusive. Here, we analyze the role of mammalian DCLK1 kinase activity in regulating microtubule binding. We found that DCLK1 autophosphorylates a residue within its C-terminal tail to restrict its kinase activity and prevent aberrant hyperphosphorylation within its microtubule-binding domain. Removal of the C-terminal tail or mutation of this residue causes an increase in phosphorylation within the doublecortin domains, which abolishes microtubule binding. Therefore, autophosphorylation at specific sites within DCLK1 has diametric effects on the molecule's association with microtubules. Our results suggest a mechanism by which DCLK1 modulates its kinase activity to tune its microtubule-binding affinity. These results provide molecular insights for future therapeutic efforts related to DCLK1's role in cancer development and progression.

Lanolin as a treatment option for ringtail in transgenic rats.

Ringtail is a condition characterized by dry skin and annular constrictions that sometimes result in loss of portions of the tail. This condition most commonly affects preweanling rats, and low relative humidity is thought to be a principal cause. The use of transgenic rats in our facility has been increasing since 2002, and we recently diagnosed several litters from transgenic Fischer 344 rats (Rattus norvegicus) with ringtail. Treatment was necessary to maintain the health and integrity of the tails to allow genotyping. Lanolin ointment was chosen because it is a nontoxic, inexpensive, effective moisturizer used for treating human skin conditions. We examined 5 litters comprising 37 pups total, ranging in age from 7 to 17 days at the time of presentation. Animals in 3 litters were randomly assigned to a treatment or nontreatment group, and all animals in the remaining 2 litters were treated. Lanolin was applied to the tails of treatment groups once daily for 6 d. Treatment was tolerated well by pups and no animals were rejected by the dams. After treatment, tail condition was scored from 0 to 3, with 0 representing a tail normal in appearance, and 3 representing severe disease. Chi square testing showed marginal statistical significance, with a trend for a higher percentage of treated rats having healthier tails on day 7 compared to untreated pups. The Pearson correlation between treatment and tail condition scores was significant. Results indicate that lanolin was an efficacious treatment option for ringtail.