Homer modulates NFAT-dependent signaling during muscle differentiation

Stiber, Jonathan A.; Tabatabaei, Niloufar; Hawkins, April; Hawke, Thomas J.; Worley, Paul F.; Williams, R. Sanders; Rosenberg, Paul B.

doi:10.1016/j.ydbio.2005.06.030

Cited by 62 publications

(78 citation statements)

References 37 publications

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“…These conditions enhanced the release of calcium from the sarcoplasmic reticulum and increased translocation of NFAT to the nucleus. The calcium/calcineurin/NFAT pathway, which had been described for muscle differentiation (9), is here shown to initiate activation of myoglobin gene expression during exercise, under both normoxic and hypoxic conditions. Figure 1 presents a schematic representation of pathways of myoglobin expression during hypoxia and during muscle contraction.…”

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confidence: 63%

Both hypoxia and work are required to enhance expression of myoglobin in skeletal muscle. Focus on “Hypoxia reprograms calcium signaling and regulates myoglobin expression”

Wittenberg

2009

American Journal of Physiology-Cell Physiology

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THE EFFECTS OF HYPOXIA on mammalian heart and muscle have fascinated physiologists for many a day. Myoglobin is expressed adaptively in muscle. In very young animals, and in the absence of muscle work, the myoglobin concentration in muscles remains very small. What factors lead to myoglobin genesis? Millikan (7) assembled a convincing body of observational and experimental evidence that sustained hard work is required for myoglobin expression. In 1962, Reynafarje (8) showed that life at high altitude favors high concentration of myoglobin in skeletal muscles of humans and small mammals. For a long time, the import of Reynafarje's findings was obscured by apparently contradictory studies showing that low oxygen pressure alone is not a sufficient stimulus for myoglobin expression. Now, Kanatous et al. (5), in the article under discussion, resolve this issue by showing that during hypoxia, myoglobin is elevated in the working heart, but not in the relatively idle skeletal musculature, of mice exposed to prolonged hypoxia. They conclude from their studies that hypoxia alone does not stimulate myoglobin expression, but that hypoxia in consort with repetitive contraction, exactly the conditions obtaining in the muscles of people residing at high altitude, does stimulate myoglobin genesis.Reversible oxygenation permits myoglobin to enhance oxygen flux from regions of high myoglobin oxygen saturation to regions of lower saturation in aqueous solution, a phenomenon named facilitated diffusion (12). This has encouraged physiologists to search for a role of intracellular myoglobin in enhancing oxygen supply to the heart and muscle mitochondria of whole animals to enhance oxidative ATP generation during hypoxia.Reversible oxygenation also permits myoglobin to function as an oxygen store, particularly in animals that work in low oxygen environments such as burrowers, animals living at high altitude, and mammals and birds performing prolonged deep sea dives (4, 6). The myoglobin content of muscles of diving animals often exceeds tenfold that apparently optimal (11) to facilitate oxygen diffusion. The myoglobin content of muscles of diving animals (4, 6) often accounts for ϳ50% of total body oxygen stores, and its concentration is directly correlated with dive duration (4). This raises the interesting question of whether the genetic mechanisms responsible for increased myoglobin expression in working muscles (5) are the same as those generating the massive myoglobin stores of diving animals. Adaptations in diving animals differ from those of the hypoxic, exercising mouse model described below. The diving animals display increased capillary density and mitochondrial volume density, adaptations that promote both diffusive and facilitated oxygen transport to the mitochondria and permit maintenance of aerobic lipid metabolism. These changes are coordinated in diving animals by increased hypoxia-inducible factor (HIF) activation. HIF, the hypoxia-inducible gene program, is a transcriptional activator of downstream target genes th...

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confidence: 63%

Both hypoxia and work are required to enhance expression of myoglobin in skeletal muscle. Focus on “Hypoxia reprograms calcium signaling and regulates myoglobin expression”

Wittenberg

2009

American Journal of Physiology-Cell Physiology

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“…Transgenic mice were generated as previously described (34,42). Adult male mice (2-4 mo old) from the two highest expressing reporter lines and wild-type littermates were used in this study.…”

Section: Methodsmentioning

confidence: 99%

“…Cells were grown on glass coverslips and differentiated over 5 days as previously described (42). Cells were then loaded with 10 M fura-2-AM (Molecular Probes, Eugene, OR) for 20 min.…”

Section: Methodsmentioning

confidence: 99%

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Hypoxia reprograms calcium signaling and regulates myoglobin expression

Kanatous¹,

Mammen²,

Rosenberg³

et al. 2009

American Journal of Physiology-Cell Physiology

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Myoglobin is an oxygen storage molecule that is selectively expressed in cardiac and slow-twitch skeletal muscles that have a high oxygen demand. Numerous studies have implicated hypoxia in the regulation of myoglobin expression as an adaptive response to hypoxic stress. However, the details of this relationship remain undefined. In the present study, adult mice exposed to 10% oxygen for periods up to 3 wk exhibited increased myoglobin expression only in the working heart, whereas myoglobin was either diminished or unchanged in skeletal muscle groups. In vitro and in vivo studies revealed that hypoxia in the presence or absence of exercise-induced stimuli reprograms calcium signaling and modulates myoglobin gene expression. Hypoxia alone significantly altered calcium influx in response to cell depolarization or depletion of endoplasmic reticulum calcium stores, which inhibited the expression of myoglobin. In contrast, our whole animal and transcriptional studies indicate that hypoxia in combination with exercise enhanced the release of calcium from the sarcoplasmic reticulum via the ryanodine receptors triggered by caffeine, which increased the translocation of nuclear factor of activated T-cells into the nucleus to transcriptionally activate myoglobin expression. The present study unveils a previously unrecognized mechanism where the hypoxia-mediated regulation of calcium transients from different intracellular pools modulates myoglobin gene expression. In addition, we observed that changes in myoglobin expression, in response to hypoxia, are not dependent on hypoxia-inducible factor-1 or changes in skeletal muscle fiber type. These studies enhance our understanding of hypoxia-mediated gene regulation and will have broad applications for the treatment of myopathic diseases. nuclear factor of activated T cells; calcineurin; skeletal muscle MYOGLOBIN IS A CYTOPLASMIC hemoprotein that is abundantly expressed in heart and oxidative skeletal myofibers. Elegant studies using physiological, biochemical, and spectroscopic analyses support an important role for myoglobin in facilitated oxygen transport, as a reservoir for oxygen and as a scavenger of reactive oxygen species in the mammalian heart and skeletal muscle (6,16,20,34,35,39). Detailed transcriptional analyses have been undertaken to define upstream activation motifs including a CCAC box, A/T element, nuclear factor of activated T cells (NFAT) response element, and E boxes that are necessary for muscle-specific transcription of the myoglobin gene (4,5,21,22). Following differentiation, myoglobin expression is coordinately regulated by neural and muscular activities that stimulate calcium signaling within the cell. Stimuli that enhance intracellular calcium levels increase activity and gene expression of calcineurin, a Ca 2ϩ /calmodulindependent serine phosphatase (13,47,48). Upon activation, calcineurin dephosphorylates the transcription factor NFAT, which translocates to the nucleus and combinatorially interacts with other transcription factors to regulate myo...

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“…Post-natal myogenesis critically relies on Ca 2ϩ influx through the SOCE pathway (1,(33)(34)(35)(36)(37). We recently established that the initiation of myoblast differentiation requires, likely among other Ca 2ϩ sources, STIM1/Orai1-dependent cytosolic Ca 2ϩ signals, which are amplified by a plasma membrane hyperpolarization (1,33,38,39).…”

Section: Stim1 and Stim2 Are Endoplasmic Reticulum (Er)mentioning

confidence: 99%

Human Muscle Economy Myoblast Differentiation and Excitation-Contraction Coupling Use the Same Molecular Partners, STIM1 and STIM2

Darbellay

Arnaudeau

Ceroni

et al. 2010

Journal of Biological Chemistry

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Our recent work identified store-operated Ca 2؉ entry (SOCE) as the critical Ca 2؉ source required for the induction of human myoblast differentiation (Darbellay, B., Arnaudeau, S., König, S., Jousset, H., Bader, C., Demaurex, N., and Bernheim, L. (2009) J. Biol. Chem. 284, 5370 -5380). The present work indicates that STIM2 silencing, similar to STIM1 silencing, reduces myoblast SOCE amplitude and differentiation. Because myoblasts in culture can be induced to differentiate into myotubes, which spontaneously contract in culture, we used the same molecular tools to explore whether the Ca 2؉ mechanism of excitation-contraction coupling also relies on STIM1 and STIM2. Live cell imaging of early differentiating myoblasts revealed a characteristic clustering of activated STIM1 and STIM2 during the first few hours of differentiation. Thapsigargin-induced depletion of endoplasmic reticulum Ca 2؉ content caused STIM1 and STIM2 redistribution into clusters, and co-localization of both STIM proteins. Interaction of STIM1 and STIM2 was revealed by a rapid increase in fluorescence resonance energy transfer between CFP-STIM1 and YFP-STIM2 after SOCE activation and confirmed by co-immunoprecipitation of endogenous STIM1 and STIM2. Although both STIM proteins clearly contribute to SOCE and are required during the differentiation process, STIM1 and STIM2 are functionally largely redundant as overexpression of either STIM1 or STIM2 corrected most of the impact of STIM2 or STIM1 silencing on SOCE and differentiation. With respect to excitation-contraction, we observed that human myotubes rely also on STIM1 and STIM2 to refill their endoplasmic reticulum Ca 2؉ -content during repeated KCl-induced Ca 2؉ releases. This indicates that STIM2 is a necessary partner of STIM1 for excitation-contraction coupling. Thus, both STIM proteins are required and interact to control SOCE during human myoblast differentiation and human myotube excitationcontraction coupling. STIM1 and STIM2 are endoplasmic reticulum (ER)2 transmembrane proteins that are activated by a drop in Ca 2ϩ content in the ER (2-5). Once activated, STIM1 and STIM2 trigger a Ca 2ϩ influx (also called store-operated Ca 2ϩ entry (SOCE)) through Ca 2ϩ -selective Orai channels located at the plasma membrane (6 -13). This Ca 2ϩ influx restores the ER Ca 2ϩ content (2-4, 10, 12, 14 -26).Several studies examined whether STIM2 had a specific role, distinct from STIM1, but no clear answer has emerged yet. A lower Ca 2ϩ -activation threshold of STIM2 as compared with STIM1 has been suggested (2), although N-terminal Ca 2ϩ -binding affinity seems to be similar for STIM1 and STIM2 (27-29). In STIM2 knock-out mice, and also in several cell types in which STIM2 has been silenced, SOCE amplitude is only slightly reduced. This could reflect either a smaller activation of Orai1 by the N-terminal part of STIM2 or a lower expression of STIM2 as compared with STIM1 (3,4,24,30). In other studies, overexpression of STIM2 has been reported to inhibit SOCE (31) or, on the contrary, to restore SOCE i...

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Homer modulates NFAT-dependent signaling during muscle differentiation

Cited by 62 publications

References 37 publications

Both hypoxia and work are required to enhance expression of myoglobin in skeletal muscle. Focus on “Hypoxia reprograms calcium signaling and regulates myoglobin expression”

Both hypoxia and work are required to enhance expression of myoglobin in skeletal muscle. Focus on “Hypoxia reprograms calcium signaling and regulates myoglobin expression”

Hypoxia reprograms calcium signaling and regulates myoglobin expression

Human Muscle Economy Myoblast Differentiation and Excitation-Contraction Coupling Use the Same Molecular Partners, STIM1 and STIM2

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