Exercise and fatigue: integrating the role of K+, Na+ and Cl- in the regulation of sarcolemmal excitability of skeletal muscle

Perturbations in K+ have long been considered a key factor in skeletal muscle fatigue. However, the exercise-induced changes in K+ intra-to-extracellular gradient is by itself insufficiently large to be a major cause for the force decrease during fatigue unless combined to other ion gradient changes such as for Na+. Whilst several studies described K+-induced force depression at high extracellular [K+] ([K+]e), others reported that small increases in [K+]e induced potentiation during submaximal activation frequencies, a finding that has mostly been ignored. There is evidence for decreased Cl- ClC-1 channel activity at muscle activity onset, which may limit K+-induced force depression, and large increases in ClC-1 channel activity during metabolic stress that may enhance K+ induced force depression. The ATP-sensitive K+ channel (KATP channel) is also activated during metabolic stress to lower sarcolemmal excitability. Taking into account all these findings, we propose a revised concept in which K+ has two physiological roles: (1) K+-induced potentiation and (2) K+-induced force depression. During low-moderate intensity muscle contractions, the K+-induced force depression associated with increased [K+]e is prevented by concomitant decreased ClC-1 channel activity, allowing K+-induced potentiation of sub-maximal tetanic contractions to dominate, thereby optimizing muscle performance. When ATP demand exceeds supply, creating metabolic stress, both KATP and ClC-1 channels are activated. KATP channels contribute to force reductions by lowering sarcolemmal generation of action potentials, whilst ClC-1 channel enhances the force-depressing effects of K+, thereby triggering fatigue. The ultimate function of these changes is to preserve the remaining ATP to prevent damaging ATP depletion

Supplement with whey protein hydrolysate in contrast to carbohydrate supports mitochondrial adaptations in trained runners

Background: Protein supplementation has been suggested to augment endurance training adaptations by increasing mixed muscle and myofibrillar protein synthesis and lean body mass. However, a potential beneficial effect on mitochondrial adaptations is yet to be clarified. The aim of the present study was to investigate the effect of consuming whey protein hydrolysate before and whey protein hydrolysate plus carbohydrate (PRO-CHO) after each exercise session during a six-week training period compared to similarly timed intake of isocaloric CHO supplements on biomarkers of mitochondrial biogenesis, VO2max and performance in trained runners. Methods: Twenty-four trained runners (VO2max 60.7 ± 3.7 ml O2 kg− 1 min1) completed a six-week block randomized controlled intervention period, consisting of progressive running training. Subjects were randomly assigned to either PRO-CHO or CHO and matched in pairs for gender, age, VO2max, training and performance status. The PRO-CHO group ingested a protein beverage (0.3 g kg− 1) before and protein-carbohydrate beverage (0.3 g protein kg− 1 and 1 g carbohydrate kg− 1) after each exercise session. The CHO group ingested an energy matched carbohydrate beverage. Resting muscle biopsies obtained pre and post intervention were analyzed for mitochondrial specific enzyme activity and mitochondrial protein content. Subjects completed a 6 K time trial (6 K TT) and a VO2max test pre, midway (only 6 K TT) and post intervention. Results: Following six weeks of endurance training Cytochrome C (Cyt C) protein content was significantly higher in the PRO-CHO group compared to the CHO group (p < 0.05), with several other mitochondrial proteins (Succinate dehydrogenase (SDHA), Cytochrome C oxidase (COX-IV), Voltage-dependent anion channel (VDAC), Heat shock protein 60 (HSP60), and Prohibitin (PHB1)) following a similar, but non-significant pattern (p = 0.07–0.14). β-hydroxyacyl-CoA dehydrogenase (HAD) activity was significantly lower after training in the CHO group (p < 0.01), but not in the PRO-CHO group (p = 0.24). VO2max and 6 K TT was significantly improved after training with no significant difference between groups. Conclusion: Intake of whey PRO hydrolysate before and whey PRO hydrolysate plus CHO after each exercise session during a six-week endurance training period may augment training effects on specific mitochondrial proteins compared to intake of iso-caloric CHO but does not alter VO2max or 6 K TT performance

A novel signalling pathway originating in mitochondria modulates rat skeletal muscle membrane excitability

Single skeletal muscle fibres from rat and cane toad were mechanically skinned and stimulated either electrically by initiating action potentials in the sealed transverse (t-) tubular system or by ion substitution causing depolarisation of the t-system to pre-determined levels. Depression of mitochondrial ATP-producing function with three diverse mitochondrial function antagonists (azide: 1–10 mm; oligomycin 1 μg ml−1 and carbonyl cyanide 4-trifluoromethoxyphenylhydrazone (FCCP) 1 μm), under conditions in which the cytosolic ATP was maintained high and constant, invariably reduced the excitability of rat fibres but had no obvious effect on the excitability of toad fibres, where mitochondria are less abundant and differently located. The reduction in excitability linked to mitochondria in rat fibres appears to be caused by depolarisation of the sealed t-system membrane. These observations suggest that mitochondria can regulate the functional state of mammalian muscle cells and have important implications for understanding how the balance between ATP utilisation and ATP production is regulated at the cellular level in general and in mammalian skeletal muscle fibres in particular

Muscle glycogen stores and fatigue

Studies performed at the beginning of the last century revealed the importance of carbohydrate as a fuel during exercise, and the importance of muscle glycogen on performance has subsequently been confirmed in numerous studies. However, the link between glycogen depletion and impaired muscle function during fatigue is not well understood and a direct cause-and-effect relationship between glycogen and muscle function remains to be established. The use of electron microscopy has revealed that glycogen is not homogeneously distributed in skeletal muscle fibres, but rather localized in distinct pools. Furthermore, each glycogen granule has its own metabolic machinery with glycolytic enzymes and regulating proteins. One pool of such glycogenolytic complexes is localized within the myofibrils in close contact with key proteins involved in the excitation–contraction coupling and Ca(2+) release from the sarcoplasmic reticulum (SR). We and others have provided experimental evidence in favour of a direct role of decreased glycogen, localized within the myofibrils, for the reduction in SR Ca(2+) release during fatigue. This is consistent with compartmentalized energy turnover and distinctly localized glycogen pools being of key importance for SR Ca(2+) release and thereby affecting muscle contractility and fatigability