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Review
. 2018 Feb 1;8(2):a029710.
doi: 10.1101/cshperspect.a029710.

Molecular Basis for Exercise-Induced Fatigue: The Importance of Strictly Controlled Cellular Ca2+ Handling

Affiliations
Review

Molecular Basis for Exercise-Induced Fatigue: The Importance of Strictly Controlled Cellular Ca2+ Handling

Arthur J Cheng et al. Cold Spring Harb Perspect Med. .

Abstract

The contractile function of skeletal muscle declines during intense or prolonged physical exercise, that is, fatigue develops. Skeletal muscle fibers fatigue acutely during highly intense exercise when they have to rely on anaerobic metabolism. Early stages of fatigue involve impaired myofibrillar function, whereas decreased Ca2+ release from the sarcoplasmic reticulum (SR) becomes more important in later stages. SR Ca2+ release can also become reduced with more prolonged, lower intensity exercise, and it is then related to glycogen depletion. Increased reactive oxygen/nitrogen species can cause long-lasting impairments in SR Ca2+ release resulting in a prolonged force depression after exercise. In this article, we discuss molecular and cellular mechanisms of the above fatigue-induced changes, with special focus on multiple mechanisms to decrease SR Ca2+ release to avoid energy depletion and preserve muscle fiber integrity. We also discuss fatigue-related effects of exercise-induced Ca2+ fluxes over the sarcolemma and between the cytoplasm and mitochondria.

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Figures

Figure 1.
Figure 1.
Three mechanisms underlying the force decrease during fatigue induced by repeated tetanic stimulation. Typical pattern of force decline (A), and selected [Ca2+]i records (B) obtained during fatigue induced by repeated tetanic stimulation in mouse flexor digitorum brevis (FDB) intact single fibers. Tetanic force initially decreases while tetanic [Ca2+]i increases (i to ii); hence, the initial force decline is caused by impaired myofibrillar function. The final force decrease is caused by reduced sarcoplasmic reticulum (SR) Ca2+ release (ii to iii). Application of caffeine facilitates SR Ca2+ release and the resulting increase in tetanic [Ca2+]i leads to a marked force increase (iv). (A and B adapted, with permission, from Lännergren and Westerblad 1991 and Westerblad and Allen 1991, respectively.) (C) The relation between force and [Ca2+]i during fatigue induced by repeated tetanic stimulation (thick line) plotted together with the force–[Ca2+]i relationship in the unfatigued state and during fatigue (thin lines). This assessment shows that acute fatigue involves initial decreases in force per cross-bridge and myofibrillar Ca2+ sensitivity, which are followed by decreased SR Ca2+ release.
Figure 2.
Figure 2.
Acidosis has no obvious effect on fatigue development, whereas fatigue is delayed when Pi accumulation is limited by inhibition of phosphocreatine breakdown. Representative records from isolated mouse flexor digitorum brevis (FDB) intact single fibers fatigued by repeated tetanic contractions. Fibers fatigued at the same rate under normal conditions (A) and after being acidified by ∼0.4 pH unit by bubbling the bath solution with 30% instead of 5% CO2 (B). (A and B adapted, with permission, from Bruton et al. 1998.) (C,D) Fatigue developed much faster in wild-type fibers than in creatine kinase–deficient (CK−/−) fibers, which cannot break down phosphocreatine and hence the accompanying increase in Pi is prevented. Representative records obtained in the first, tenth, and last (88th) fatiguing tetanic contraction in a wild-type fiber; the CK−/− fiber showed no fatigue during 100 tetanic contraction. (C and D adapted, with permission, from Dahlstedt et al. 2000.)
Figure 3.
Figure 3.
Cellular mechanisms of decreased sarcoplasmic reticulum (SR) Ca2+ release in acute fatigue. (A) Increases in the cytoplasmic concentration of Mg2+ and Pi, as well as decreased ATP, can directly inhibit action potential-DHPR-mediated RyR1 opening. (B) When myoplasmic [Pi] increases, some Pi can enter the SR and form Ca2+-Pi precipitates that reduce the free Ca2+ available for release ([Ca2+]SR). (C) Action potential propagation can be impaired by extracellular K+ accumulation, as well as increased opening of Cl (ClC-1) and ATP-sensitive K+ (KATP) channels. Red plus and minus symbols indicate excitatory or inhibitory influence on channels, respectively. DHPR, Dihydropyridine receptor; RyR1, ryanodine receptor 1; [K+]o, extracellular [K+]; [K+]i, intracellular [K+].
Figure 4.
Figure 4.
The decrease in tetanic [Ca2+]i and force during fatigue induced by repeated tetanic contractions was not affected by the presence of reactive oxygen species (ROS)/reactive nitrogen species (RNS)-modulating compounds, whereas the delayed recovery process is ROS/RNS-sensitive. Typical fatigue profiles of [Ca2+]i (A), and force (B) from an intact single flexor digitorum brevis (FDB) fiber stimulated with repeated tetanic contractions. Relative tetanic [Ca2+]i (C), and force (D) at the end of fatiguing stimulation in standard Tyrode solution (control) compared with exposure to the NADPH-oxidase 2 (NOX-2) inhibitor gp91ds-tat; the NOX-4 inhibitor GKT137831; the mitochondrial-targeted antioxidant SS-31; the nitric oxide synthase (NOS) inhibitor L-NAME; and antioxidant-NOS-inhibitor cocktail. Data are mean ± SEM; dashed red lines indicate no difference from control. One-way ANOVA showed no difference between groups for either [Ca2+]i or force. Representative records of [Ca2+]i (upper row) and force (lower row) obtained in one control fiber (E) and one fiber superfused with mitochondrial-targeted antioxidant SS-31 (F) and stimulated at submaximal frequency (30 Hz) before (Pre) and 5 and 30 min after fatiguing stimulation. Note that the prolonged low-frequency force depression (PLFFD) was related to decreased tetanic [Ca2+]i in control but not in the presence of SS-31 (indicated by red dashed lines). (Adapted, with permission, from Cheng et al. 2015.)
Figure 5.
Figure 5.
Ca2+ fluxes during contractions of skeletal muscle fibers. The contractile machinery of muscle fibers is triggered by Ca2+ released from the sarcoplasmic reticulum (SR) via the ryanodine receptor 1 (RyR1) Ca2+ channels. The absolute majority of Ca2+ ions are actively pumped back into SR by the SR Ca2+ pumps (SERCA). Few Ca2+ ions are extruded from the cell via the plasma membrane Ca2+ (PMCA) pumps or Na+-Ca2+ exchangers (NCX); the Ca2+ extrusion is balanced mainly by store-operated Ca2+ entry, which involves the SR Ca2+ sensor, the stromal-interacting molecule 1 (STIM1) that activates the sarcolemmal Orai1 Ca2+ channels. Some Ca2+ ions may enter the mitochondrial matrix mainly via the tightly controlled mitochondrial Ca2+ uniporter (MCU) and these are subsequently returned to the myoplasm via mitochondrial Na+-Ca2+ exchangers (NCLX).

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