ECC meets CEU—New focus on the backdoor for calcium ions in skeletal muscle cells

Melzer, Werner

doi:10.1085/jgp.202012679

Cited by 3 publications

(3 citation statements)

References 43 publications

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“…The sites of STIM1/Orai1 interaction in skeletal muscle fibers has been long debated, as initially it was proposed that SOCE would occur in triads, the intracellular junctions deputed to EC coupling [ 17 ]. Though, this initial hypothesis was not confirmed by recent experimental evidence collected in our laboratory between 2017 and 2020 [ 44 , 47 , 48 , 49 , 50 , 51 , 52 ]. New intracellular junctions named Ca 2+ entry units (CEUs), formed by the association of TT and SR at the I band, were identified as the sites of interaction between STIM1 and Orai1 during SOCE.…”

Section: Introductionmentioning

confidence: 66%

Store-Operated Ca2+ Entry in Skeletal Muscle Contributes to the Increase in Body Temperature during Exertional Stress

Girolami

Serano

Michelucci

et al. 2022

IJMS

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Exertional heat stroke (HS) is a hyperthermic crisis triggered by an excessive accumulation of Ca2+ in skeletal muscle fibers. We demonstrated that exercise leads to the formation of calcium entry units (CEUs), which are intracellular junctions that reduce muscle fatigue by promoting the recovery of extracellular Ca2+ via store-operated Ca2+ entry (SOCE). Here, we tested the hypothesis that exercise-induced assembly of CEUs may increase the risk of HS when physical activity is performed in adverse environmental conditions (high temperature and humidity). Adult mice were: (a) first, divided into three experimental groups: control, trained-1 month (voluntary running in wheel cages), and acutely exercised-1 h (incremental treadmill run); and (b) then subjected to an exertional stress (ES) protocol, a treadmill run in an environmental chamber at 34°C and 40% humidity. The internal temperature of the mice at the end of the ES was higher in both pre-exercised groups. During an ES ex-vivo protocol, extensor digitorum longus(EDL) muscles from the trained-1 month and exercised-1 h mice generated greater basal tension than in the control and were those that contained a greater number of CEUs, assessed by electron microscopy. The data collected suggest that the entry of Ca2+ from extracellular space via CEUs could contribute to exertional HS when exercise is performed in adverse environmental conditions.

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Section: Introductionmentioning

confidence: 66%

Store-Operated Ca2+ Entry in Skeletal Muscle Contributes to the Increase in Body Temperature during Exertional Stress

Girolami

Serano

Michelucci

et al. 2022

IJMS

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“…A commentary published in J. Gen. Physiol. proposed CEUs as the backdoor for Ca 2+ ions in muscle cells, bringing new attention to the importance of external Ca 2+ in the function skeletal fibers [208].…”

Section: Calcium Entry Units (Ceus): the Dynamic Junctions That Media...mentioning

confidence: 99%

Improper Remodeling of Organelles Deputed to Ca2+ Handling and Aerobic ATP Production Underlies Muscle Dysfunction in Ageing

Protasi

Pietrangelo

Boncompagni

2021

IJMS

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Proper skeletal muscle function is controlled by intracellular Ca2+ concentration and by efficient production of energy (ATP), which, in turn, depend on: (a) the release and re-uptake of Ca2+ from sarcoplasmic-reticulum (SR) during excitation–contraction (EC) coupling, which controls the contraction and relaxation of sarcomeres; (b) the uptake of Ca2+ into the mitochondrial matrix, which stimulates aerobic ATP production; and finally (c) the entry of Ca2+ from the extracellular space via store-operated Ca2+ entry (SOCE), a mechanism that is important to limit/delay muscle fatigue. Abnormalities in Ca2+ handling underlie many physio-pathological conditions, including dysfunction in ageing. The specific focus of this review is to discuss the importance of the proper architecture of organelles and membrane systems involved in the mechanisms introduced above for the correct skeletal muscle function. We reviewed the existing literature about EC coupling, mitochondrial Ca2+ uptake, SOCE and about the structural membranes and organelles deputed to those functions and Finally, we summarized the data collected in different, but complementary, projects studying changes caused by denervation and ageing to the structure and positioning of those organelles: a. denervation of muscle fibers—an event that contributes, to some degree, to muscle loss in ageing (known as sarcopenia)—causes misplacement and damage: (i) of membrane structures involved in EC coupling (calcium release units, CRUs) and (ii) of the mitochondrial network; b. sedentary ageing causes partial disarray/damage of CRUs and of calcium entry units (CEUs, structures involved in SOCE) and loss/misplacement of mitochondria; c. functional electrical stimulation (FES) and regular exercise promote the rescue/maintenance of the proper architecture of CRUs, CEUs, and of mitochondria in both denervation and ageing. All these structural changes were accompanied by related functional changes, i.e., loss/decay in function caused by denervation and ageing, and improved function following FES or exercise. These data suggest that the integrity and proper disposition of intracellular organelles deputed to Ca2+ handling and aerobic generation of ATP is challenged by inactivity (or reduced activity); modifications in the architecture of these intracellular membrane systems may contribute to muscle dysfunction in ageing and sarcopenia.

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“…While there was always general agreement about the important role that SOCE plays in limiting muscle fatigue [ 40 , 41 , 50 , 51 , 77 ], exactly how and where STIM1/Orai1 interact to allow Ca 2+ entry in skeletal muscle fibers has been debated for several years. Recent experimental evidence collected in our laboratory indicated that intracellular junctions, named Ca 2+ Entry Units (CEUs), formed by the association of SR and TT at the I band, are the most likely sites of interaction between STIM1 and Orai1 during SOCE [ 77 , 78 , 79 , 80 , 81 , 82 , 83 ]. CEUs are few and small in control conditions (the main reason that did not allow their prompt identification), but increase in number and size during exercise [ 77 ] to then disassemble following recovery [ 81 ].…”

Section: Introductionmentioning

confidence: 99%

Searching for Mechanisms Underlying the Assembly of Calcium Entry Units: The Role of Temperature and pH

Girolami

Serano

Fonso

et al. 2023

IJMS

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Store-operated Ca2+ entry (SOCE) is a mechanism that allows muscle fibers to recover external Ca2+, which first enters the cytoplasm andthen, via SERCA pump, also refills the depleted intracellular stores (i.e., the sarcoplasmic reticulum, SR). We recently discovered that SOCE is mediated by Calcium Entry Units (CEUs), intracellular junctions formed by: (i) SR stacks containing STIM1; and (ii) I-band extensions of the transverse tubule (TT) containing Orai1. The number and size of CEUs increase during prolonged muscle activity, though the mechanisms underlying exercise-dependent formation of new CEUs remain to be elucidated. Here, we first subjected isolated extensor digitorum longus (EDL) muscles from wild type mice to an exvivo exercise protocol and verified that functional CEUs can assemble alsoin the absence of blood supply and innervation. Then, we evaluated whetherparameters that are influenced by exercise, such as temperature and pH, may influence the assembly of CEUs. Results collected indicate that higher temperature (36 °C vs. 25 °C) and lower pH (7.2 vs. 7.4) increase the percentage of fibers containing SR stacks, the n. of SR stacks/area, and the elongation of TTs at the I band. Functionally, assembly of CEUs at higher temperature (36 °C) or at lower pH (7.2) correlates with increased fatigue resistance of EDL muscles in the presence of extracellular Ca2+. Taken together, these results indicate that CEUs can assemble in isolated EDL muscles and that temperature and pH are two of the possible regulators of CEU formation.

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ECC meets CEU—New focus on the backdoor for calcium ions in skeletal muscle cells

Cited by 3 publications

References 43 publications

Store-Operated Ca2+ Entry in Skeletal Muscle Contributes to the Increase in Body Temperature during Exertional Stress

Store-Operated Ca2+ Entry in Skeletal Muscle Contributes to the Increase in Body Temperature during Exertional Stress

Improper Remodeling of Organelles Deputed to Ca2+ Handling and Aerobic ATP Production Underlies Muscle Dysfunction in Ageing

Searching for Mechanisms Underlying the Assembly of Calcium Entry Units: The Role of Temperature and pH

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