Calcineurin Activates Cytoglobin Transcription in Hypoxic Myocytes

Singh, Sarvjeet; Manda, Shilpa M.; Sikder, Devanjan; Birrer, Michael J.; Rothermel, Beverly A.; Garry, Daniel J.; Mammen, Pradeep P.A.

doi:10.1074/jbc.m809572200

Cited by 31 publications

(32 citation statements)

References 60 publications

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“…C2C12 myoblasts were plated in equal numbers under normoxic conditions as previously described (24). MPCs were isolated and cultured from the hindlimbs of 8-wk-old male mice as previously described (83).…”

Section: Methodsmentioning

confidence: 99%

“…Proteins from cell lysates, cellular fractions (i.e., nuclear and cytosolic), or whole-muscle tissue were isolated from control and experimental groups. Western blot analysis was performed as previously described (24,28,68). Total RNA, RT-PCR, and qRT-PCR were performed as previously described (24 Tables S1 and S2.…”

Section: Methodsmentioning

confidence: 99%

“…Cygb is a heme-containing protein of the globin family that is structurally similar to myoglobin (Mb) and is conserved across species (mammals, fish, amphibians, reptiles, and birds) (26,27). In mammals it is expressed in a variety of tissues, including skeletal muscle, although the Cygb transcript level in the adult skeletal muscle is low compared with the levels in heart and brain (24,(26)(27)(28)(29). Mechanistic studies defining the function of Cygb are limited.…”

mentioning

confidence: 99%

“…Recently, we demonstrated that hypoxia induces the expression of the gene encoding cytoglobin (Cygb) in C2C12 myoblasts, an immortalized cell line derived from MPCs (24,25). Cygb is a heme-containing protein of the globin family that is structurally similar to myoglobin (Mb) and is conserved across species (mammals, fish, amphibians, reptiles, and birds) (26,27).…”

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confidence: 99%

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Cytoglobin modulates myogenic progenitor cell viability and muscle regeneration

Singh¹,

Canseco²,

Manda³

et al. 2013

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

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Mammalian skeletal muscle can remodel, repair, and regenerate itself by mobilizing satellite cells, a resident population of myogenic progenitor cells. Muscle injury and subsequent activation of myogenic progenitor cells is associated with oxidative stress. Cytoglobin is a hemoprotein expressed in response to oxidative stress in a variety of tissues, including striated muscle. In this study, we demonstrate that cytoglobin is up-regulated in activated myogenic progenitor cells, where it localizes to the nucleus and contributes to cell viability. siRNA-mediated depletion of cytoglobin from C2C12 myoblasts increased levels of reactive oxygen species and apoptotic cell death both at baseline and in response to stress stimuli. Conversely, overexpression of cytoglobin reduced reactive oxygen species levels, caspase activity, and cell death. Mice in which cytoglobin was knocked out specifically in skeletal muscle were generated to examine the role of cytoglobin in vivo. Myogenic progenitor cells isolated from these mice were severely deficient in their ability to form myotubes as compared with myogenic progenitor cells from wild-type littermates. Consistent with this finding, the capacity for muscle regeneration was severely impaired in mice deficient for skeletal-muscle cytoglobin. Collectively, these data demonstrate that cytoglobin serves an important role in muscle repair and regeneration.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Cytoglobin modulates myogenic progenitor cell viability and muscle regeneration

Singh¹,

Canseco²,

Manda³

et al. 2013

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

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“…Myoglobin is phylogenetically most similar to cytoglobin, another monomeric hemoprotein that is ubiquitously expressed in all vertebrate tissues (Burmester et al, 2002;Singh et al, 2009;Trent and Hargrove, 2002). Myoglobin, cytoglobin and hemoglobin are believed to have shared a common ancestral globin more than 500 million years ago (Burmester et al, 2002).…”

Section: Myoglobin Genomic Organization and Gene Structurementioning

confidence: 99%

Regulation of myoglobin expression

Kanatous

Mammen

2010

Journal of Experimental Biology

105

101

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SUMMARY Myoglobin is a well-characterized, cytoplasmic hemoprotein that is expressed primarily in cardiomyocytes and oxidative skeletal muscle fibers. However, recent studies also suggest low-level myoglobin expression in various non-muscle tissues. Prior studies incorporating molecular, pharmacological, physiological and transgenic technologies have demonstrated that myoglobin is an essential oxygen-storage hemoprotein capable of facilitating oxygen transport and modulating nitric oxide homeostasis within cardiac and skeletal myocytes. Concomitant with these studies, scientific investigations into the transcriptional regulation of myoglobin expression have been undertaken. These studies have indicated that activation of key transcription factors (MEF2, NFAT and Sp1) and co-activators (PGC-1α) by locomotor activity, differential intracellular calcium fluxes and low intracellular oxygen tension collectively regulate myoglobin expression. Future studies focused on tissue-specific transcriptional regulatory pathways and post-translational modifications governing myoglobin expression will need to be undertaken. Finally, further studies investigating the modulation of myoglobin expression under various myopathic processes may identify myoglobin as a novel therapeutic target for the treatment of various cardiac and skeletal myopathies.

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Regulation of Cellular Gas Exchange, Oxygen Sensing, and Metabolic Control

Clanton

Hogan

Gladden

2013

Comprehensive Physiology

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Cells must continuously monitor and couple their metabolic requirements for ATP utilization with their ability to take up O2 for mitochondrial respiration. When O2 uptake and delivery move out of homeostasis, cells have elaborate and diverse sensing and response systems to compensate. In this review, we explore the biophysics of O2 and gas diffusion in the cell, how intracellular O2 is regulated, how intracellular O2 levels are sensed and how sensing systems impact mitochondrial respiration and shifts in metabolic pathways. Particular attention is paid to how O2 affects the redox state of the cell, as well as the NO, H2S, and CO concentrations. We also explore how these agents can affect various aspects of gas exchange and activate acute signaling pathways that promote survival. Two kinds of challenges to gas exchange are also discussed in detail: when insufficient O2 is available for respiration (hypoxia) and when metabolic requirements test the limits of gas exchange (exercising skeletal muscle). This review also focuses on responses to acute hypoxia in the context of the original "unifying theory of hypoxia tolerance" as expressed by Hochachka and colleagues. It includes discourse on the regulation of mitochondrial electron transport, metabolic suppression, shifts in metabolic pathways, and recruitment of cell survival pathways preventing collapse of membrane potential and nuclear apoptosis. Regarding exercise, the issues discussed relate to the O2 sensitivity of metabolic rate, O2 kinetics in exercise, and influences of available O2 on glycolysis and lactate production.

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Calcineurin Activates Cytoglobin Transcription in Hypoxic Myocytes

Cited by 31 publications

References 60 publications

Cytoglobin modulates myogenic progenitor cell viability and muscle regeneration

Cytoglobin modulates myogenic progenitor cell viability and muscle regeneration

Regulation of myoglobin expression

Regulation of Cellular Gas Exchange, Oxygen Sensing, and Metabolic Control

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