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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The biological mechanisms underlying decline in muscle power and fatigue with age are not completely understood. The contribution of alterations in the excitation-calcium release coupling in single muscle fibers was explored in this work. Single muscle fibers were voltage-clamped using the double Vaseline gap technique. The samples were obtained by needle biopsy of the vastus lateralis (quadriceps) from 9 young (25-35 years; 25.9 +/- 9.1; 5 female and 4 male) and 11 old subjects (65-75 years; 70.5 +/- 2.3; 6 f, 5 m). Data were obtained from 36 and 39 fibers from young and old subjects, respectively. Subjects included in this study had similar physical activity. Denervated and slow-twitch muscle fibers were excluded from this study. A significant reduction of maximum charge movement (Qmax) and DHP-sensitive Ca current were recorded in muscle fibers from the 65-75 group. Qmax values were 7.6 +/- 0.9 and 3.2 +/- 0.3 nC/muF for young and old muscle fibers, respectively (P < 0.01). No evidences of charge inactivation or interconversion (charge 1 to charge 2) were found. The peak Ca current was (-)4.7 +/- 0.08 and (-)2.15 +/- 0.11 muA/muF for young and old fibers, respectively (P < 0.01). The peak calcium transient studied with mag-fura-2 (400 microM) was 6.3 +/- 0.4 microM and 4.2 +/- 0.3 microM for young and old muscle fibers, respectively. Caffeine (0.5 mM) induced potentiation of the peak calcium transient in both groups. The decrease in the voltage-/Ca-dependent Ca release ratio in old fibers (0.18 +/- 0.02) compared to young fibers (0.47 +/- 0.03) (P < 0.01), was recorded in the absence of sarcoplasmic reticulum calcium depletion. These data support a significant reduction of the amount of Ca available for triggering mechanical responses in aged skeletal muscle and, the reduction of Ca release is due to DHPR-ryanodine receptor uncoupling in fast-twitch fibers. These alterations can account, at least partially for the skeletal muscle function impairment associated with aging.
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PMID:Excitation-calcium release uncoupling in aged single human skeletal muscle fibers. 874 53

1. Raising the intracellular [Ca2+] for 10 s at 23 degrees C abolished depolarization-induced force responses in mechanically skinned muscle fibres of toad and rat (half-maximal effect at 10 and 23 microM, respectively), without affecting the ability of caffeine or low [Mg2+] to open the ryanodine receptor (RyR)/Ca2+ release channels. Thus, excitation-contraction coupling was lost, even though the Ca2+ release channels were still functional. Coupling could not be restored in the duration of an experiment (up to 1 h). 2. The Ca(2+)-dependent uncoupling had a Q10 > 3.5, and was three times slower at pH 5.8 than at pH 7.1. Sr2+ caused similar uncoupling at twenty times higher concentration, but Mg2+, even at 10 mM, was ineffective. Uncoupling was not noticeably affected by removal of ATP or application of protein kinase or phosphatase inhibitors. 3. Confocal laser scanning microscopy showed that the transverse tubular system was sealed in its entirety in mechanically skinned fibres and that its integrity was maintained in uncoupled fibres. Electron microscopy revealed distorted or severed triad junctions and Z-line aberrations in uncoupled fibres. 4. Only when uncoupling was induced at a relatively slow rate (e.g. over 60 s with 2.5 microM Ca2+) could it be prevented by the protease inhibitor leupeptin (1 mM). Immunostaining of Western blots showed no evidence of proteolysis of the RyR, the alpha 1-subunit of dihydropyridine receptor (DHPR) or triadin in uncoupled fibres. 5. Fibres which, whilst intact, were stimulated repeatedly by potassium depolarization with simultaneous application of 30 mM caffeine showed reduced responsiveness after skinning to depolarization but not to caffeine. Rapid release of endogenous Ca2+, or raised [Ca2+] under conditions which minimized the loss of endogenous diffusible myoplasmic molecules from the skinned fibre, caused complete uncoupling. Taken together, these results suggest that Ca(2+)-dependent uncoupling can also occur in intact fibres. 6. This Ca(2+)-dependent loss of depolarization-induced Ca2+ release may play an important feedback role in muscle by stopping Ca2+ release in localized areas where it is excessive and may be responsible for long-lasting muscle fatigue after severe exercise, as well as contributing to muscle weakness in various dystrophies.
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PMID:Raised intracellular [Ca2+] abolishes excitation-contraction coupling in skeletal muscle fibres of rat and toad. 884 31

The mechanisms underlying skeletal muscle functional impairment and structural changes with advanced age are only partially understood. In the present study, we support and expand our theory about alterations in sarcolemmal excitation-sarcoplasmic reticulum Ca2+ release-contraction uncoupling as a primary skeletal muscle alteration and major determinant of weakness and fatigue in mammalian species including humans. To test the hypothesis that the number of RYR1 (ryanodine receptor) uncoupled to DHPR (dihydropyridine receptor) increases with age, we performed high-affinity ligand binding studies in soleus, extensor digitorum longus (EDL) and in a pool of several skeletal muscles consisting of a mixture of fast- and slow-twitch muscle fibers in middle-aged (14-month) and old (28-months) Fisher 344 Brown Norway F1 hybrids rats. The number of DHPR, RYR1, the coupling between both receptors expressed as the DHPR/RYR1 maximum binding capacity, and their dissociation constant for high-affinity ligands were measured. The DHPR/RYR1 ratio was significantly reduced in the three groups of muscles (pool: 1.03 +/- 0.15 and 0.80 +/- 0.11, soleus: 0.44 +/- 0. 12 and 0.26 +/- 0.10, and EDL: 0.95 +/- 0.14 and 0.68 +/- 0.10, for middle-aged and old muscles, respectively). These data support the concept that DHPR-RYR1 uncoupling results in alterations in the voltage-gated sarcoplasmic reticulum Ca2+ release mechanism, decreases in myoplasmic Ca2+ elevation in response to sarcolemmal depolarization, reduced Ca2+ supply to contractile proteins and reduced contraction force with aging.
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PMID:Dihydropyridine receptor-ryanodine receptor uncoupling in aged skeletal muscle. 917 12

To examine mechanisms underlying force reduction after the onset of chronic low-frequency (10 Hz) stimulation (CLFS), we exposed rabbit tibialis anterior muscles to various durations of CLFS. To follow changes in isometric contractile properties and electromyographic (EMG) activity, we studied stimulated and contralateral muscles during a terminal test at 10 Hz for 10 min. In addition, activities and protein amounts of the sarcoplasmic reticulum Ca(2+)-ATPase, content of Na(+)-K(+)-ATPase, and expression patterns of triad junction components were examined. Force output and EMG amplitude declined abruptly soon after the onset of stimulation, suggesting refractoriness of a large fiber population. Although twitch force and to a lesser extent EMG activity gradually recovered after stimulation for 6 days and longer, the muscles exhibited profoundly altered properties, i.e., enhanced fatigue resistance, absence of twitch potentiation, and prolonged contraction and relaxation times. These changes were associated with significant increases in Na(+)-K(+)-ATPase concentration and significant decreases in Ca(2+)-ATPase, ryanodine receptor, dihydropyridine receptor, and triadin concentrations over the course of the 20 days of stimulation. Alterations in excitability, Ca2+ handling, and excitation-contraction coupling prior to changes in myofibrillar protein isoforms may thus be responsible for early functional alterations.
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PMID:Early functional and biochemical adaptations to low-frequency stimulation of rabbit fast-twitch muscle. 925 68

Calcium signalling in cells is dependent on a communication between channels/ transporters in two membrane structures: the cell membrane and the membranes of endo- and sarcoplasmic reticula (ER/SR). In general, cytosolic Ca2+ can be raised by influx of calcium over the cell membrane through three types of channels: voltage-, receptor-, and store-operated channels (VOCs, ROCs and SOCs). This small Ca2+ influx is most often amplified by a Ca2+ release from the ER/SR through two types of channels: the IP3-receptor and the ryanodine receptor (RyR), which are huge proteins identified and cloned in recent years. We focus on the 'synaptic' connection between VOCs (L-type calcium channels) and RyRs of the SR in heart and skeletal muscle. Depolarization of the cell membrane (an action potential) opens the VOC and moves it in the membrane. One VOC triggers opening of a certain number of underlying RyRs that together release a quantum of calcium from the SR, a calcium spark. The communication between the VOC and RyRs is probably achieved primarily by a mechanical link in skeletal muscle (voltage-controlled calcium release), and by the small inward calcium flux through the VOC in the heart (calcium-induced calcium release, CICR). Conditions as different as heart failure, myasthenia gravis, malignant hyperthermia, and skeletal muscle fatigue, may be examples of deteriorated control or function of the RyR.
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PMID:Intracellular calcium signalling in striated muscle cells. 939 86

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 aerobic to fast anaerobic physiology. In addition, skeletal muscle exhibits high plasticity that is based on the potential of the muscle fibers to undergo changes of their cytoarchitecture and composition of specific muscle protein isoforms. Adaptive changes of the muscle fibers occur in response to a variety of stimuli such as, e.g., growth and differentition factors, hormones, nerve signals, or exercise. Additionally, the muscle fibers are arranged in compartments that often function as largely independent muscular subunits. All muscle fibers use Ca(2+) as their main regulatory and signaling molecule. Therefore, contractile properties of muscle fibers are dependent on the variable expression of proteins involved in Ca(2+) signaling and handling. Molecular diversity of the main proteins in the Ca(2+) signaling apparatus (the calcium cycle) largely determines the contraction and relaxation properties of a muscle fiber. The Ca(2+) signaling apparatus includes 1) the ryanodine receptor that is the sarcoplasmic reticulum Ca(2+) release channel, 2) the troponin protein complex that mediates the Ca(2+) effect to the myofibrillar structures leading to contraction, 3) the Ca(2+) pump responsible for Ca(2+) reuptake into the sarcoplasmic reticulum, and 4) calsequestrin, the Ca(2+) storage protein in the sarcoplasmic reticulum. In addition, a multitude of Ca(2+)-binding proteins is present in muscle tissue including parvalbumin, calmodulin, S100 proteins, annexins, sorcin, myosin light chains, beta-actinin, calcineurin, and calpain. These Ca(2+)-binding proteins may either exert an important role in Ca(2+)-triggered muscle contraction under certain conditions or modulate other muscle activities such as protein metabolism, differentiation, and growth. Recently, several Ca(2+) signaling and handling molecules have been shown to be altered in muscle diseases. Functional alterations of Ca(2+) handling seem to be responsible for the pathophysiological conditions seen in dystrophinopathies, Brody's disease, and malignant hyperthermia. These also underline the importance of the affected molecules for correct muscle performance.
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PMID:Calcium ion in skeletal muscle: its crucial role for muscle function, plasticity, and disease. 1089 34

In this review, potential roles for the endogenous sphingolipid, sphingosine, and its derivatives are described for muscle cells. Sphingosine modulates the function of important calcium channels in muscle, including the ryanodine receptor (RyR) calcium release channel of the sarcoplasmic reticulum (SR). Sphingosine blocks calcium release through the SR ryanodine receptor and reduces the activity of single skeletal muscle RyR channels reconstituted into planar lipid bilayers. Sphingosine-blocked calcium release is coincident with the inhibitory effects of sphingosine on [3H]ryanodine binding to the RyR. The sphingomyelin signal transduction pathway has also been identified in both skeletal and cardiac muscle. A neutral form of sphingomyelinase (nSMase) enzyme has been localized to the junctional transverse tubule membrane. The high turnover of the SMase is responsible for the production of ceramide and sphingosine. HPLC analyses indicate that significant resting levels of sphingosine are present in muscle tissue. A model of excitation-contraction coupling is presented suggesting a potential role for this endogenous sphingolipid in normal muscle function. Putative roles for sphingolipid mediators in skeletal muscle dysfunction are also discussed. We hypothesize that sphingosine plays important roles in malignant hyperthermia and during the development of muscle fatigue.
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PMID:The role of sphingolipids in the control of skeletal muscle function: a review. 1093 63

The store-operated calcium channel (SOC) located in the plasma membrane (PM) mediates capacitative entry of extracellular calcium after depletion of intracellular calcium stores in the endoplasmic or sarcoplasmic reticulum (ER/SR). An intimate interaction between the PM and the ER/SR is essential for the operation of this calcium signalling pathway. Mitsugumin 29 (MG29) is a synaptophysin-family-related protein located in the junction between the PM and SR of skeletal muscle. Here, we identify SOC in skeletal muscle and characterise its regulation by MG29 and the ryanodine receptor (RyR) located in the SR. Targeted deletion of mg29 alters the junctional membrane structure, causes severe dysfunction of SOC and SR calcium homeostasis and increases the susceptibility of muscle to fatigue stimulation. Severe dysfunction of SOC is also identified in muscle cells lacking both type 1 and type 3 RyRs, indicating that SOC activation requires an intact interaction between the PM and the SR, and is linked to conformational changes of RyRs. Whereas defective SOC seems to be inconsequential to short-term excitation-contraction coupling, the slow cumulative calcium entry through SOC is crucial for long-term calcium homeostasis, such that reduced SOC activity exaggerates muscle fatigue under conditions of intensive exercise.
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PMID:Dysfunction of store-operated calcium channel in muscle cells lacking mg29. 1198 40

We studied whether hydrogen peroxide (H(2)O(2)) at </=10 microM activates the ryanodine receptor and decreases releasable Ca(2+) content in the sarcoplasmic reticulum after fatigue. Exposure of rabbit or frog skeletal muscle ryanodine receptors to 10 microM H(2)O(2) enhanced channel activity in lipid bilayers when the redox potential was defined at cis = -220 mV and trans = -180 mV. Channel activation by 10 microM H(2)O(2) was also observed when cis potential was set at -220 mV without defining trans potential, but the effect was less. Reduction of trans redox potential from -180 to -220 mV did not alter channel activity. H(2)O(2) at 500 microM failed to activate the channel when the redox potential was not controlled. Stimulation of the frog muscle fiber for 2 min (50 Hz, a duty cycle of 200 ms/s) decreased tetanus tension by approximately 50%. After 1 min, tetanus recovered rapidly to approximately 70% of control and thereafter slowly approached the control level. Amplitudes of caffeine- and 4-chloro-m-cresol-induced contractures were decreased after a 60-min rest. The decrease is not enhanced by exposure to 10 microM H(2)O(2). These results suggest that H(2)O(2) markedly activates the ryanodine receptor under the redox control in vitro, but externally applied H(2)O(2) may not play an important role in the postfatigue recovery process.
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PMID:H2O2 activates ryanodine receptor but has little effect on recovery of releasable Ca2+ content after fatigue. 1239 Nov 5

The type 1 ryanodine receptor (RyR1) on the sarcoplasmic reticulum (SR) is the major calcium (Ca2+) release channel required for skeletal muscle excitation-contraction (EC) coupling. RyR1 function is modulated by proteins that bind to its large cytoplasmic scaffold domain, including the FK506 binding protein (FKBP12) and PKA. PKA is activated during sympathetic nervous system (SNS) stimulation. We show that PKA phosphorylation of RyR1 at Ser2843 activates the channel by releasing FKBP12. When FKB12 is bound to RyR1, it inhibits the channel by stabilizing its closed state. RyR1 in skeletal muscle from animals with heart failure (HF), a chronic hyperadrenergic state, were PKA hyperphosphorylated, depleted of FKBP12, and exhibited increased activity, suggesting that the channels are "leaky." RyR1 PKA hyperphosphorylation correlated with impaired SR Ca2+ release and early fatigue in HF skeletal muscle. These findings identify a novel mechanism that regulates RyR1 function via PKA phosphorylation in response to SNS stimulation. PKA hyperphosphorylation of RyR1 may contribute to impaired skeletal muscle function in HF, suggesting that a generalized EC coupling myopathy may play a role in HF.
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PMID:PKA phosphorylation activates the calcium release channel (ryanodine receptor) in skeletal muscle: defective regulation in heart failure. 1262 52


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