Repeated, intense use of muscles leads to a decline in performance known as muscle fatigue. Many muscle properties change during fatigue including the action potential, extracellular and intracellular ions, and many intracellular metabolites. A range of mechanisms have been identified that contribute to the decline of performance. The traditional explanation, accumulation of intracellular lactate and hydrogen ions causing impaired function of the contractile proteins, is probably of limited importance in mammals. Alternative explanations that will be considered are the effects of ionic changes on the action potential, failure of SR Ca2+ release by various mechanisms, and the effects of reactive oxygen species. Many different activities lead to fatigue, and an important challenge is to identify the various mechanisms that contribute under different circumstances. Most of the mechanistic studies of fatigue are on isolated animal tissues, and another major challenge is to use the knowledge generated in these studies to identify the mechanisms of fatigue in intact animals and particularly in human diseases.

/pdf/skeletal-muscle-fatigue-cellular-mechanisms-d0dzk4w31g.pdf

Skeletal Muscle Fatigue: Cellular Mechanisms

The ryanodine receptors (RyRs) are a family of Ca2+ release channels found on intracellular Ca2+ storage/release organelles. The RyR channels are ubiquitously expressed in many types of cells and participate in a variety of important Ca2+ signaling phenomena (neurotransmission, secretion, etc.). In striated muscle, the RyR channels represent the primary pathway for Ca2+ release during the excitation-contraction coupling process. In general, the signals that activate the RyR channels are known (e.g., sarcolemmal Ca2+ influx or depolarization), but the specific mechanisms involved are still being debated. The signals that modulate and/or turn off the RyR channels remain ambiguous and the mechanisms involved unclear. Over the last decade, studies of RyR-mediated Ca2+ release have taken many forms and have steadily advanced our knowledge. This robust field, however, is not without controversial ideas and contradictory results. Controversies surrounding the complex Ca2+ regulation of single RyR channels receive particular attention here. In addition, a large body of information is synthesized into a focused perspective of single RyR channel function. The present status of the single RyR channel field and its likely future directions are also discussed.

https://www.physiology.org/doi/pdf/10.1152/physrev.00013.2002

Ryanodine Receptor Calcium Release Channels

Mammalian skeletal muscle shows an enormous variability in its functional features such as rate of force production, resistance to fatigue, and energy metabolism, with a wide spectrum from slow aer...

Calcium Ion in Skeletal Muscle: Its Crucial Role for Muscle Function, Plasticity, and Disease

Cysteine Proteases and Their Inhibitors.

The cardiac ryanodine receptor (RyR2)/calcium release channel on the sarcoplasmic reticulum is required for muscle excitation-contraction coupling. Using site-directed mutagenesis, we identified th...

Ca2+/Calmodulin-Dependent Protein Kinase II Phosphorylation Regulates the Cardiac Ryanodine Receptor

Isolated skeletal muscle triads contain a compartmentalized glycolytic reaction sequence catalyzed by aldolase, triosephosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase, and phosphoglycerate kinase. These enzymes express activity in the structure-associated state leading to synthesis of ATP in the triadic junction upon supply of glyceraldehyde 3-phosphate or fructose 1,6-bisphosphate. ATP formation occurs transiently and appears to be kinetically compartmentalized, i.e., the synthesized ATP is not in equilibrium with the bulk ATP. The apparent rate constants of the aldolase and the glyceraldehyde-3-phosphate dehydrogenase/phosphoglycerate kinase reaction are significantly increased when fructose 1,6-bisphosphate instead of glyceraldehyde 3-phosphate is employed as substrate. The observations suggest that fructose 1,6-bisphosphate is especially effectively channelled into the junctional gap. The amplitude of the ATP transient is decreasing with increasing free [Ca2+] in the range of 1 nM to 30 microM. In the presence of fluoride, the ATP transient is significantly enhanced and its declining phase is substantially retarded. This observation suggests utilization of endogenously synthesized ATP in part by structure associated protein kinases and phosphatases which is confirmed by the detection of phosphorylated triadic proteins after gel electrophoresis and autoradiography. Endogenous protein kinases phosphorylate proteins of apparent Mr 450,000, 180,000, 160,000, 145,000, 135,000, 90,000, 54,000, 51,000, and 20,000, respectively. Some of these phosphorylated polypeptides are in the Mr range of known phosphoproteins involved in excitation-contraction coupling of skeletal muscle, which might give a first hint at the functional importance of the sequential glycolytic reactions compartmentalized in triads.

Compartmentalized ATP synthesis in skeletal muscle triads.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2896%2900442-5

VDAC/porin is present in sarcoplasmic reticulum from skeletal muscle

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2893%2980640-G

Enhancement of Ca2+ release channel activity by phosphorylation of the skeletal muscle ryanodine receptor

https://www.cell.com/biophysj/pdf/S0006-3495(05)73393-2.pdf

Regulation of Ryanodine Receptors by Calsequestrin: Effect of High Luminal Ca2+ and Phosphorylation

In striated muscle, the sarcoplasmic reticulum (SR) Ca2+ release/ryanodine receptor (RyR) channel provides the pathway through which stored Ca2+ is released into the myoplasm during excitation-contraction coupling. Various luminal Ca2+-binding proteins are responsible for maintaining the free [Ca2+] at 10(-3)-10(-4) M in the SR lumen; in skeletal-muscle SR, it is mainly calsequestrin. Here we show that, depending on its phosphorylation state, calsequestrin selectively controls the RyR channel activity at 1 mM free luminal [Ca2+]. Calsequestrin exclusively in the dephosphorylated state enhanced the open probability by approx. 5-fold with a Hill coefficient (h) of 3.3, and increased the mean open time by about 2-fold, i.e. solely dephosphorylated calsequestrin regulates Ca2+ release from the SR. Because calsequestrin has been found to occur mainly in the phosphorylated state in the skeletal-muscle SR for the regulation of RyR channel activity, the dephosphorylation of calsequestrin would appear to be a quintessential physiological event.

Magdolna Varsányi

Papers

Compartmentalized ATP synthesis in skeletal muscle triads.

VDAC/porin is present in sarcoplasmic reticulum from skeletal muscle

Enhancement of Ca2+ release channel activity by phosphorylation of the skeletal muscle ryanodine receptor

Regulation of Ryanodine Receptors by Calsequestrin: Effect of High Luminal Ca2+ and Phosphorylation

Calsequestrin: More than 'only' a luminal Ca2+ buffer inside the sarcoplasmic reticulum