Phosphoinositides in Ca2+ signaling and excitation–contraction coupling in skeletal muscle: an old player and newcomers

Csernoch, László; Jacquemond, Vincent

doi:10.1007/s10974-015-9422-4

Cited by 6 publications

(5 citation statements)

References 90 publications

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“…The activation of the PIP 2 Ca 2+ signaling system controls diverse cellular processes in numerous tissues [48]. In skeletal muscle the sarcoplasmic reticulum ryanodine receptor is the Ca 2+ release channel, however, PIP 2 has been localized to the transverse tubular membrane, and IP 3 receptors have been found in differentiated muscle fibers and implicated in excitation-contraction coupling (for review see Csernoch et al [49]). Thus, FRMD8 may play a role in Ca 2+ signaling and excitation-contraction coupling of skeletal muscles through interactions with PIP 2 .…”

Section: Discussionmentioning

confidence: 99%

Genetic control of longissimus dorsi muscle gene expression variation and joint analysis with phenotypic quantitative trait loci in pigs

et al. 2019

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BackgroundEconomically important growth and meat quality traits in pigs are controlled by cascading molecular events occurring during development and continuing throughout the conversion of muscle to meat. However, little is known about the genes and molecular mechanisms involved in this process. Evaluating transcriptomic profiles of skeletal muscle during the initial steps leading to the conversion of muscle to meat can identify key regulators of polygenic phenotypes. In addition, mapping transcript abundance through genome-wide association analysis using high-density marker genotypes allows identification of genomic regions that control gene expression, referred to as expression quantitative trait loci (eQTL). In this study, we perform eQTL analyses to identify potential candidate genes and molecular markers regulating growth and meat quality traits in pigs.ResultsMessenger RNA transcripts obtained with RNA-seq of longissimus dorsi muscle from 168 F2 animals from a Duroc x Pietrain pig resource population were used to estimate gene expression variation subject to genetic control by mapping eQTL. A total of 339 eQTL were mapped (FDR ≤ 0.01) with 191 exhibiting local-acting regulation. Joint analysis of eQTL with phenotypic QTL (pQTL) segregating in our population revealed 16 genes significantly associated with 21 pQTL for meat quality, carcass composition and growth traits. Ten of these pQTL were for meat quality phenotypes that co-localized with one eQTL on SSC2 (8.8-Mb region) and 11 eQTL on SSC15 (121-Mb region). Biological processes identified for co-localized eQTL genes include calcium signaling (FERM, MRLN, PKP2 and CHRNA9), energy metabolism (SUCLG2 and PFKFB3) and redox hemostasis (NQO1 and CEP128), and results support an important role for activation of the PI3K-Akt-mTOR signaling pathway during the initial conversion of muscle to meat.ConclusionCo-localization of eQTL with pQTL identified molecular markers significantly associated with both economically important phenotypes and gene transcript abundance. This study reveals candidate genes contributing to variation in pig production traits, and provides new knowledge regarding the genetic architecture of meat quality phenotypes.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-5386-2) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Genetic control of longissimus dorsi muscle gene expression variation and joint analysis with phenotypic quantitative trait loci in pigs

et al. 2019

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“…In addition to this primary Ca 2ϩ signaling pathway, skeletal muscle retains the InsP 3 /Ca 2ϩ signaling pathway that drove development to regulate processes both in the nucleus and in the cytoplasm (83). There appear to be two mechanisms responsible for activating the PLC that generates InsP 3 : it is activated by insulin (82) and by membrane depolarization (213,382).…”

Section: A Skeletal Musclementioning

confidence: 99%

The Inositol Trisphosphate/Calcium Signaling Pathway in Health and Disease

Berridge

2016

Physiological Reviews

578

452

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Many cellular functions are regulated by calcium (Ca(2+)) signals that are generated by different signaling pathways. One of these is the inositol 1,4,5-trisphosphate/calcium (InsP3/Ca(2+)) signaling pathway that operates through either primary or modulatory mechanisms. In its primary role, it generates the Ca(2+) that acts directly to control processes such as metabolism, secretion, fertilization, proliferation, and smooth muscle contraction. Its modulatory role occurs in excitable cells where it modulates the primary Ca(2+) signal generated by the entry of Ca(2+) through voltage-operated channels that releases Ca(2+) from ryanodine receptors (RYRs) on the internal stores. In carrying out this modulatory role, the InsP3/Ca(2+) signaling pathway induces subtle changes in the generation and function of the voltage-dependent primary Ca(2+) signal. Changes in the nature of both the primary and modulatory roles of InsP3/Ca(2+) signaling are a contributory factor responsible for the onset of a large number human diseases.

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“…6). For instance, knockdown of the PtdInsP phosphatase MTMR14, which uses the same substrates as MTM1, affects EC coupling in zebrafish without structure defects (17).…”

Section: Discussionmentioning

confidence: 99%

“…How MTM1 deficiency is responsible for defective EC coupling remains unclear, and this issue is highly relevant to understanding the mechanisms of the disease but also to gaining insights into the interactions between phosphoinositides and Ca 2+ signaling in muscle (see ref. 6). The Mtm1-KO mouse model reproduces the main symptomatic features of the human disease: Mutant mice develop a progressive myopathy that starts at about 3-4 wk of age, leading to death 3-5 wk later (7).…”

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confidence: 99%

Phosphatidylinositol 3-kinase inhibition restores Ca ²⁺ release defects and prolongs survival in myotubularin-deficient mice

Kutchukian

Scrudato

Tourneur

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in the gene encoding the phosphoinositide 3-phosphatase myotubularin (MTM1) are responsible for a pediatric disease of skeletal muscle named myotubular myopathy (XLMTM). Muscle fibers from MTM1-deficient mice present defects in excitation-contraction (EC) coupling likely responsible for the disease-associated fatal muscle weakness. However, the mechanism leading to EC coupling failure remains unclear. During normal skeletal muscle EC coupling, transverse (t) tubule depolarization triggers sarcoplasmic reticulum (SR) Ca 2+ release through ryanodine receptor channels gated by conformational coupling with the t-tubule voltage-sensing dihydropyridine receptors. We report that MTM1 deficiency is associated with a 60% depression of global SR Ca 2+ release over the full range of voltage sensitivity of EC coupling. SR Ca 2+ release in the diseased fibers is also slower than in normal fibers, or delayed following voltage activation, consistent with the contribution of Ca 2+ -gated ryanodine receptors to EC coupling. In addition, we found that SR Ca 2+ release is spatially heterogeneous within myotubularin-deficient muscle fibers, with focally defective areas recapitulating the global alterations. Importantly, we found that pharmacological inhibition of phosphatidylinositol 3-kinase (PtdIns 3-kinase) activity rescues the Ca 2+ release defects in isolated muscle fibers and increases the lifespan and mobility of XLMTM mice, providing proof of concept for the use of PtdIns 3-kinase inhibitors in myotubular myopathy and suggesting that unbalanced PtdIns 3-kinase activity plays a critical role in the pathological process.skeletal muscle | excitation-contraction coupling | ryanodine receptor | sarcoplasmic reticulum Ca 2+ release | myotubularin I mpaired skeletal muscle excitation-contraction (EC) coupling is believed to be a main cause of the severe muscle weakness associated with myotubular myopathy (1). EC coupling operates through interactions between the voltage-sensing CAV1.1 Ca 2+ channel (also known as the dihydropyridine receptor) in the transverse (t) tubule membrane and the type 1 ryanodine receptor (RYR1) Ca 2+ release channel in the junctional sarcoplasmic reticulum (SR) membrane: Opening of RYR1 channels under the control of the CAV1.1 voltage-sensing activity is responsible for the Ca 2+ flux that raises cytosolic Ca 2+ to trigger contraction (2, 3). Myotubular myopathy is due to genetic deficiency in the phosphoinositide (phosphatidylinositol, PtdInsP) phosphatase MTM1, which dephosphorylates PtdIns(3,5)P 2 and PtdIns(3)P at the D3 position of the inositol ring (4, 5). How MTM1 deficiency is responsible for defective EC coupling remains unclear, and this issue is highly relevant to understanding the mechanisms of the disease but also to gaining insights into the interactions between phosphoinositides and Ca 2+ signaling in muscle (see ref. 6). The Mtm1-KO mouse model reproduces the main symptomatic features of the human disease: Mutant mice develop a progressive myopathy that starts at about 3-4 wk of ...

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Phosphoinositides in Ca2+ signaling and excitation–contraction coupling in skeletal muscle: an old player and newcomers

Cited by 6 publications

References 90 publications

Genetic control of longissimus dorsi muscle gene expression variation and joint analysis with phenotypic quantitative trait loci in pigs

Genetic control of longissimus dorsi muscle gene expression variation and joint analysis with phenotypic quantitative trait loci in pigs

The Inositol Trisphosphate/Calcium Signaling Pathway in Health and Disease

Phosphatidylinositol 3-kinase inhibition restores Ca ²⁺ release defects and prolongs survival in myotubularin-deficient mice

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Phosphoinositides in Ca2+ signaling and excitation–contraction coupling in skeletal muscle: an old player and newcomers

Cited by 6 publications

References 90 publications

Genetic control of longissimus dorsi muscle gene expression variation and joint analysis with phenotypic quantitative trait loci in pigs

Genetic control of longissimus dorsi muscle gene expression variation and joint analysis with phenotypic quantitative trait loci in pigs

The Inositol Trisphosphate/Calcium Signaling Pathway in Health and Disease

Phosphatidylinositol 3-kinase inhibition restores Ca 2+ release defects and prolongs survival in myotubularin-deficient mice

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Phosphatidylinositol 3-kinase inhibition restores Ca ²⁺ release defects and prolongs survival in myotubularin-deficient mice