Significance: High-intensity interval training (HIIT) has become popular because it is a time-efficient way to increase endurance. An intriguing and so-far-unanswered question is how a few minutes of HIIT can be that effective. We exposed recreationally active men to one session of three to six sets of 30-s high-intensity cycling exercise. Muscle biopsies taken 24 h later showed an extensive fragmentation of the sarcoplasmic reticulum (SR) Ca ²⁺ channels, the ryanodine receptor 1 (RyR1). In isolated mouse muscle fibers, this fragmentation was accompanied by increased SR Ca ²⁺ leak, which can trigger mitochondrial biogenesis. The HIIT-induced RyR1 fragmentation did not occur in muscles exposed to antioxidant, which offers an explanation for why antioxidants blunt effects of endurance training.

We compared the extent and origin of muscle fatigue induced by short-pulse-low-frequency [conventional (CONV)] and wide-pulse-high-frequency (WPHF) neuromuscular electrical stimulation. We expected CONV contractions to mainly originate from depolarization of axonal terminal branches (spatially determined muscle fiber recruitment) and WPHF contractions to be partly produced via a central pathway (motor unit recruitment according to size principle). Greater neuromuscular fatigue was, therefore, expected following CONV compared with WPHF. Fourteen healthy subjects underwent 20 WPHF (1 ms-100 Hz) and CONV (50 μs-25 Hz) evoked isometric triceps surae contractions (work/rest periods 20:40 s) at an initial target of 10% of maximal voluntary contraction (MVC) force. Force-time integral of the 20 evoked contractions (FTI) was used as main index of muscle fatigue; MVC force loss was also quantified. Central and peripheral fatigue were assessed by voluntary activation level and paired stimulation amplitudes, respectively. FTI in WPHF was significantly lower than in CONV (21,717 ± 11,541 vs. 37,958 ± 9,898 N·s P<0,001). The reductions in MVC force (WPHF: −7.0 ± 2.7%; CONV: −6.2 ± 2.5%; P < 0.01) and paired stimulation amplitude (WPHF: −8.0 ± 4.0%; CONV: −7.4 ± 6.1%; P < 0.001) were similar between conditions, whereas no change was observed for voluntary activation level ( P > 0.05). Overall, our results showed a different motor unit recruitment pattern between the two neuromuscular electrical stimulation modalities with a lower FTI indicating greater muscle fatigue for WPHF, possibly limiting the presumed benefits for rehabilitation programs.

The extent and characteristics of muscle fatigue of different muscle groups when subjected to a similar fatiguing task may differ. Thirteen healthy young men performed sustained contractions at 50% maximal voluntary contraction (MVC) force until task failure, with four different muscle groups, over two sessions. Per session, one upper limb and one lower limb muscle group were tested (knee extensors and thumb adductor, or plantar and elbow flexors). Changes in voluntary activation level and contractile properties were derived from doublet responses evoked during and after MVCs before and after exercise. Time to task failure differed ( P < 0.05) between muscle groups (220 ± 64 s for plantar flexors, 114 ± 27 s for thumb adductor, 77 ± 25 s for knee extensors, and 72 ± 14 s for elbow flexors). MVC force loss immediately after voluntary task failure was similar (−30 ± 11% for plantar flexors, −37 ± 13% for thumb adductor, −34 ± 15% for knee extensors, and −40 ± 12% for elbow flexors, P > 0.05). Voluntary activation was decreased for plantar flexors only (from 95 ± 5% to 82 ± 9%, P < 0.05). Potentiated evoked doublet amplitude was more depressed for upper limb muscles (−59.3 ± 14.7% for elbow flexors and −60.1 ± 24.1% for thumb adductor, P < 0.05) than for knee extensors (−28 ± 15%, P < 0.05); no reduction was found in plantar flexors (−7 ± 12%, P > 0.05). In conclusion, despite different times to task failure when sustaining an isometric contraction at 50% MVC force for as long as possible, diverse muscle groups present similar loss of MVC force after task failure. Thus the extent of muscle fatigue is not affected by time to task failure, whereas this latter determines the etiology of fatigue.

Skeletal muscle wasting is a devastating consequence of cancer that contributes to increased complications and poor survival, but is not well understood at the molecular level. Herein, we investigated the role of Myocilin (Myoc), a skeletal muscle hypertrophy-promoting protein that we showed is downregulated in multiple mouse models of cancer cachexia. Loss of Myoc alone was sufficient to induce phenotypes identified in mouse models of cancer cachexia, including muscle fiber atrophy, sarcolemmal fragility, and impaired muscle regeneration. By 18 months of age, mice deficient in Myoc showed significant skeletal muscle remodeling, characterized by increased fat and collagen deposition compared with wild-type mice, thus also supporting Myoc as a regulator of muscle quality. In cancer cachexia models, maintaining skeletal muscle expression of Myoc significantly attenuated muscle loss, while mice lacking Myoc showed enhanced muscle wasting. Furthermore, we identified the myocyte enhancer factor 2 C (MEF2C) transcription factor as a key upstream activator of Myoc whose gain of function significantly deterred cancer-induced muscle wasting and dysfunction in a preclinical model of pancreatic ductal adenocarcinoma (PDAC). Finally, compared with noncancer control patients, MYOC was significantly reduced in skeletal muscle of patients with PDAC defined as cachectic and correlated with MEF2c. These data therefore identify disruptions in MEF2c-dependent transcription of Myoc as a novel mechanism of cancer-associated muscle wasting that is similarly disrupted in muscle of patients with cachectic cancer. Significance: This work identifies a novel transcriptional mechanism that mediates skeletal muscle wasting in murine models of cancer cachexia that is disrupted in skeletal muscle of patients with cancer exhibiting cachexia.

L voluntary exhaustion, an isometric contraction with their right knee extensor muscles at a target force equal to 20% of their maximal voluntary contraction (MVC) force. At task failure, the muscle was immediately electrically stimulated for 1 min aiming the same target force (20% MVC force). Subsequently, subjects were asked to resume the voluntary contraction for as long as possible. Knee extensor neuromuscular function was assessed before and after the entire protocol for comparison. Results When electrically stimulated at the point of task failure, all subjects developed the 20% MVC force target, indicating that lack of force-generating capacity from peripheral impairment had not limited the duration of the first task. We observed a reduction in MVC force after the entire protocol (−57% ± 12%), which correlated with a decrease in potentiated peak doublet force (−48% ± 17%, P < 0.001). The level of voluntary activation, as quantified with the interpolated twitch technique, was slightly depressed after the entire protocol (from 93% ± 7% to 87% ± 10%, P < 0.01). Conclusions It follows that task failure from a sustained isometric contraction is mainly affected by central/motivational factors, whereas MVC force loss is largely explained by the extent of contractile failure of the muscle....