High-intensity interval training (HIIT) is a time-efficient way of improving physical performance in healthy subjects and in patients with common chronic diseases, but less so in elite endurance athletes. The mechanisms underlying the effectiveness of HIIT are uncertain. Here, recreationally active human subjects performed highly demanding HIIT consisting of 30-s bouts of all-out cycling with 4-min rest in between bouts (≤3 min total exercise time). Skeletal muscle biopsies taken 24 h after the HIIT exercise showed an extensive fragmentation of the sarcoplasmic reticulum (SR) Ca 2+ release channel, the ryanodine receptor type 1 (RyR1). The HIIT exercise also caused a prolonged force depression and triggered major changes in the expression of genes related to endurance exercise. Subsequent experiments on elite endurance athletes performing the same HIIT exercise showed no RyR1 fragmentation or prolonged changes in the expression of endurance-related genes. Finally, mechanistic experiments performed on isolated mouse muscles exposed to HIIT-mimicking stimulation showed reactive oxygen/nitrogen species (ROS)-dependent RyR1 fragmentation, calpain activation, increased SR Ca 2+ leak at rest, and depressed force production due to impaired SR Ca 2+ release upon stimulation. In conclusion, HIIT exercise induces a ROSdependent RyR1 fragmentation in muscles of recreationally active subjects, and the resulting changes in muscle fiber Ca 2+ -handling trigger muscular adaptations. However, the same HIIT exercise does not cause RyR1 fragmentation in muscles of elite endurance athletes, which may explain why HIIT is less effective in this group.ryanodine receptor 1 | high-intensity exercise | skeletal muscle | Ca 2+ | reactive oxygen species

Physical exercise has emerged as an alternative treatment for patients with depressive disorder. Recent animal studies show that exercise protects from depression by increased skeletal muscle kynurenine aminotransferase (KAT) expression which shifts the kynurenine metabolism away from the neurotoxic kynurenine (KYN) to the production of kynurenic acid (KYNA). In the present study, we investigated the effect of exercise on kynurenine metabolism in humans. KAT gene and protein expression was increased in the muscles of endurance-trained subjects compared with untrained subjects. Endurance exercise caused an increase in plasma KYNA within the first hour after exercise. In contrast, a bout of high-intensity eccentric exercise did not lead to increased plasma KYNA concentration. Our results show that regular endurance exercise causes adaptations in kynurenine metabolism which can have implications for exercise recommendations for patients with depressive disorder.

The coactivator PGC-1α1 is activated by exercise training in skeletal muscle and promotes fatigue-resistance. In exercised muscle, PGC-1α1 enhances the expression of kynurenine aminotransferases (Kats), which convert kynurenine into kynurenic acid. This reduces kynurenine-associated neurotoxicity and generates glutamate as a byproduct. Here, we show that PGC-1α1 elevates aspartate and glutamate levels and increases the expression of glycolysis and malate-aspartate shuttle (MAS) genes. These interconnected processes improve energy utilization and transfer fuel-derived electrons to mitochondrial respiration. This PGC-1α1-dependent mechanism allows trained muscle to use kynurenine metabolism to increase the bioenergetic efficiency of glucose oxidation. Kat inhibition with carbidopa impairs aspartate biosynthesis, mitochondrial respiration, and reduces exercise performance and muscle force in mice. Our findings show that PGC-1α1 activates the MAS in skeletal muscle, supported by kynurenine catabolism, as part of the adaptations to endurance exercise. This crosstalk between kynurenine metabolism and the MAS may have important physiological and clinical implications.

Combined androgenic-anabolic steroids (AAS) and overloading affects tendon collagen metabolism and ultrastructure and is often associated with a higher risk of injury. The aim of this prospective study was to investigate whether such effects would be reflected in the patellar tendon properties of individuals with a history of long-term resistance training and AAS abuse (RTS group), compared with trained (RT) and untrained (CTRL) nonsteroids users. Tendon cross-sectional area (CSA), stiffness, Young's modulus, and toe limit strain were measured in vivo, from synchronized ultrasonography and dynamometry data. The patellar tendon of RT and RTS subjects was much stiffer and larger than in the CTRL group. However, stiffness and modulus were higher in the RTS group (26%, P < 0.05 and 30%, P < 0.01, respectively) than in the RT group. Conversely, tendon CSA was 15% (P < 0.05) larger in the RT group than in RTS, although differences disappeared when this variable was normalized to quadriceps maximal isometric torque. Yet maximal tendon stress was higher in RTS than in RT (15%, P < 0.05), without any statistical difference in maximal strain and toe limit strain between groups. The present lack of difference in toe limit strain does not substantiate the hypothesis of changes in collagen crimp pattern associated with AAS abuse. However, these findings indicate that tendon adaptations from years of heavy resistance training are different in AAS users, suggesting differences in collagen remodeling. Some of these adaptations (e.g., higher stress) could be linked to a higher risk of tendon injury.

PurposeForce production frequently remains depressed for several hours or even days after various types of strenuous physical exercise. We hypothesized that the pattern of force changes during the first hour after exercise can be used to reveal muscular mechanisms likely to underlie the decline in muscle performance during exercise as well as factors involved in the triggering the prolonged force depression after exercise.MethodsNine groups of recreationally active male volunteers performed one of the following types of exercise: single prolonged or repeated short maximum voluntary contractions (MVCs); single or repeated all-out cycling bouts; repeated drop jumps. The isometric force of the right quadriceps muscle was measured during stimulation with brief 20 and 100 Hz trains of electrical pulses given before and at regular intervals for 60 min after exercise.ResultsAll exercises resulted in a prolonged force depression, which was more marked at 20 Hz than at 100 Hz. Short-lasting (≤2 min) MVC and all-out cycling exercises showed an initial force recovery (peak after ~ 5 min) followed by a secondary force depression. The repeated drop jumps, which involve eccentric contractions, resulted in a stable force depression with the 20 Hz force being markedly more decreased after 100 than 10 jumps.ConclusionsIn accordance with our hypothesis, the results propose at least three different mechanisms that influence force production after exercise: (1) a transiently recovering process followed by (2) a prolonged force depression after metabolically demanding exercise, and (3) a stable force depression after mechanically demanding contractions.