Mitochondrial activity regulates myoblast differentiation by control of c‐Myc expression

Seyer, Pascal; Grandemange, Stéphanie; Busson, Muriel; Carazo, Ángel; Gamaléri, Frédéric; Pessemesse, Laurence; Casas, François; Cabello, Gérard; Wrutniak‐Cabello, Chantal

doi:10.1002/jcp.20539

Cited by 74 publications

(81 citation statements)

References 58 publications

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“…How PGC-1α, a transcriptional coactivator, can exert repressive effects remains elusive. A previous study revealed that stimulation of mitochondrial activity diminishes Myc expression (36). Conceivably, the PGC-1α-mediated boost in mitochondrial activity might repress Myc expression analogously.…”

Section: 2)mentioning

confidence: 90%

Skeletal muscle PGC-1α controls whole-body lactate homeostasis through estrogen-related receptor α-dependent activation of LDH B and repression of LDH A

Summermatter

Santos

Pérez-Schindler

et al. 2013

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

131

108

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The peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) controls metabolic adaptations. We now show that PGC-1α in skeletal muscle drives the expression of lactate dehydrogenase (LDH) B in an estrogen-related receptor-α-dependent manner. Concomitantly, PGC-1α reduces the expression of LDH A and one of its regulators, the transcription factor myelocytomatosis oncogene. PGC-1α thereby coordinately alters the composition of the LDH complex and prevents the increase in blood lactate during exercise. Our results show how PGC-1α actively coordinates lactate homeostasis and provide a unique molecular explanation for PGC-1α-mediated muscle adaptations to training that ultimately enhance exercise performance and improve metabolic health.transcriptional regulation | mitochondria | oxidative metabolism | metabolic reprogramming | muscle plasticity

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Section: 2)mentioning

confidence: 90%

Skeletal muscle PGC-1α controls whole-body lactate homeostasis through estrogen-related receptor α-dependent activation of LDH B and repression of LDH A

Summermatter

Santos

Pérez-Schindler

et al. 2013

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

131

108

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“…The significance of coordinated mitochondrial expansion is underscored by the critical role of nucleusmitochondria interaction in promoting muscle-specific gene expression, thereby securing myogenic differentiation. 31 The hypothesis that cardiac development is dependent on mitochondrial function was further validated using the respiratory chain inhibitors antimycin or rotenone, which disrupted proper cardiogenesis but still gave rise to viable embryoid bodies. Furthermore, the state of mitochondrial activation influences the intracellular redox potential.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial oxidative metabolism is required for the cardiac differentiation of stem cells

Chung¹,

Dzeja²,

Faustino³

et al. 2007

Nat Rev Cardiol

465

482

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SUMMARYCardiogenesis within embryos or associated with heart repair requires stem cell differentiation into energetically competent, contracting cardiomyocytes. While it is widely accepted that the coordination of genetic circuits with developmental bioenergetics is critical to phenotype specification, the metabolic mechanisms that drive cardiac transformation are largely unknown. Here, we aim to define the energetic requirements for and the metabolic microenvironment needed to support the cardiac differentiation of embryonic stem cells. We demonstrate that anaerobic glycolytic metabolism, while sufficient for embryonic stem cell homeostasis, must be transformed into the more efficient mitochondrial oxidative metabolism to secure cardiac specification and excitation-contraction coupling. This energetic switch was programmed by rearrangement of the metabolic transcriptome that encodes components of glycolysis, fatty acid oxidation, the Krebs cycle, and the electron transport chain. Modifying the copy number of regulators of mitochondrial fusion and fission resulted in mitochondrial maturation and network expansion, which in turn provided an energetic continuum to supply nascent sarcomeres. Disrupting respiratory chain function prevented mitochondrial organization and compromised the energetic infrastructure, causing deficient sarcomerogenesis and contractile malfunction. Thus, establishment of the mitochondrial system and engagement of oxidative metabolism are prerequisites for the differentiation of stem cells into a functional cardiac phenotype. Mitochondria-dependent energetic circuits are thus critical regulators of de novo cardiogenesis and targets for heart regeneration.

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“…TFAM is a key transcription factor responsible for both the replication and transcription of mitochondrial DNA (57); thus, its downregulation in Smad3-null regenerated muscle indicates defective mitochondrial biogenesis. Previous studies suggest an essential role for mitochondria in muscle regeneration, where mitochondria are required for myoblast proliferation and differentiation in addition to its primary function in energy metabolism (54,60). In vivo muscle regeneration studies have indicated that expression of mitochondrial biogenesis-related genes is synchronized with the expression of myogenic genes, such as MyoD and Myogenin (13,68).…”

Section: E98mentioning

confidence: 97%

Lack of Smad3 signaling leads to impaired skeletal muscle regeneration

Vajjala

McFarlane

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Smad3 is a key intracellular signaling mediator for both transforming growth factor-β and myostatin, two major regulators of skeletal muscle growth. Previous published work has revealed pronounced muscle atrophy together with impaired satellite cell functionality in Smad3-null muscles. In the present study, we have further validated a role for Smad3 signaling in skeletal muscle regeneration. Here, we show that Smad3-null mice had incomplete recovery of muscle weight and myofiber size after muscle injury. Histological/immunohistochemical analysis suggested impaired inflammatory response and reduced number of activated myoblasts during the early stages of muscle regeneration in the tibialis anterior muscle of Smad3-null mice. Nascent myofibers formed after muscle injury were also reduced in number. Moreover, Smad3-null regenerated muscle had decreased oxidative enzyme activity and impaired mitochondrial biogenesis, evident by the downregulation of the gene encoding mitochondrial transcription factor A, a master regulator of mitochondrial biogenesis. Consistent with known Smad3 function, reduced fibrotic tissue formation was also seen in regenerated Smad3-null muscle. In conclusion, Smad3 deficiency leads to impaired muscle regeneration, which underscores an essential role of Smad3 in postnatal myogenesis. Given the negative role of myostatin during muscle regeneration, the increased expression of myostatin observed in Smad3-null muscle may contribute to the regeneration defects.

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Mitochondrial activity regulates myoblast differentiation by control of c‐Myc expression

Cited by 74 publications

References 58 publications

Skeletal muscle PGC-1α controls whole-body lactate homeostasis through estrogen-related receptor α-dependent activation of LDH B and repression of LDH A

Skeletal muscle PGC-1α controls whole-body lactate homeostasis through estrogen-related receptor α-dependent activation of LDH B and repression of LDH A

Mitochondrial oxidative metabolism is required for the cardiac differentiation of stem cells

Lack of Smad3 signaling leads to impaired skeletal muscle regeneration

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