Physiological activation of hypoxia inducible factor‐1 in human skeletal muscle

Ameln, Helene; Gustafsson, Thomas; Sundberg, Carl Johan; Okamoto, Kensaku; Jansson, Eva; Poellinger, Lorenz; Makino, Yuichi

doi:10.1096/fj.04-2304fje

Cited by 222 publications

(205 citation statements)

References 38 publications

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“…This PGC-1␣-induced mitochondrial biogenesis prepares the muscle for the next bout of exercise, with an increased oxidative phosphorylation capacity, resulting in greater capacity for endurance training. HIF-1 ␣ protein levels also increase markedly in skeletal muscle in response to a single bout of exercise (45), and the effect of PGC-1␣ on HIF-1 that we describe here may prolong the activity of HIF-1 allowing for a sustained adaptive response to exercise. Finally, skeletal musclespecific HIF-1␣ knock out mice demonstrate that the increased expression of HIF target genes normally observed in response to exercise is HIF-1 dependent, suggesting a role for HIF in the adaptation of skeletal muscle in response to exercise (46).…”

Section: Discussionmentioning

confidence: 53%

PGC-1α is coupled to HIF-1α-dependent gene expression by increasing mitochondrial oxygen consumption in skeletal muscle cells

O'Hagan

Cocchiglia

Zhdanov

et al. 2009

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

171

133

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Mitochondrial biogenesis occurs in response to increased cellular ATP demand. The mitochondrial electron transport chain requires molecular oxygen to produce ATP. Thus, increased ATP generation after mitochondrial biogenesis results in increased oxygen demand that must be matched by a corresponding increase in oxygen supply. We found that overexpression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), which increases mitochondrial biogenesis in primary skeletal muscle cells, leads to increased expression of a cohort of genes known to be regulated by the dimeric hypoxia-inducible factor (HIF), a master regulator of the adaptive response to hypoxia. PGC-1α-dependent induction of HIF target genes under physiologic oxygen concentrations is not through transcriptional coactivation of HIF or up-regulation of HIF-1α mRNA but through HIF-1α protein stabilization. It occurs because of intracellular hypoxia as a result of increased oxygen consumption after mitochondrial biogenesis. Thus, we propose that at physiologic oxygen concentrations, PGC-1α is coupled to HIF signaling through the regulation of intracellular oxygen availability, allowing cells and tissues to match increased oxygen demand after mitochondrial biogenesis with increased oxygen supply.

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Section: Discussionmentioning

confidence: 53%

PGC-1α is coupled to HIF-1α-dependent gene expression by increasing mitochondrial oxygen consumption in skeletal muscle cells

O'Hagan

Cocchiglia

Zhdanov

et al. 2009

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

171

133

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“…29,30 Increased HIF-1␣ has been reported during strenuous physical activity. 31,32 The release of s-HJV to suppress hepcidin could be a signal to meet the increased iron requests for myoglobin synthesis, during both differentiation and hypoxia caused by physical activity 29,30 in order to preserve muscle oxygen homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis

Silvestri

Pagani

Camaschella

2008

Blood

273

275

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The liver peptide hepcidin regulates iron absorption and recycling. Hemojuvelin (HJV) has a key role in hepcidin regulation, and its inactivation causes severe iron overload both in humans and in mice. Membrane HJV (m-HJV) acts as a coreceptor for bone morphogenetic proteins (BMPs), whereas soluble HJV (s-HJV) may down-regulate hepcidin in a competitive way interfering with BMP signaling. s-HJV is decreased by iron in vitro and increased by iron deficiency in vivo. IntroductionThe liver peptide hepcidin is the key regulator of systemic iron homeostasis 1 since it determines the level of circulating iron controlling intestinal iron absorption and macrophage iron recycling. Hemojuvelin (HJV) is a recently recognized protein that plays a crucial role in the regulation of hepcidin. The HJV gene, encoding HJV, is the gene of 1q-linked juvenile hemochromatosis, a recessive disease that leads to severe iron overload of early onset (hemochromatosis type 2A, OMIM no. 602390). 2 Patients with mutated HJV as well as Hjv Ϫ/Ϫ mice 3,4 have low/absent hepcidin levels, indicating that HJV modulates hepcidin. HJV is expressed in liver, skeletal muscle, and heart 2 and belongs to the family of repulsive guidance molecules (RGMs), expressed mainly in the central nervous system. 5,6 As are the other RGM proteins, HJV is characterized by a signal peptide, a RGD motif, a partial von Willebrand factor type D domain, and a glycosilphosphatidylinositol (GPI)-anchor domain. 2 HJV undergoes a partial autocatalytic cleavage 7 to reach the plasma membrane (m-HJV) as a cleaved heterodimer. 8,9 Recently, it was shown that HJV is a coreceptor for bone morphogenetic proteins (BMPs) and that hepcidin regulation occurs via the BMP/SMAD pathway. 10,11 BMP2 and BMP4 signaling is dependent on diferric transferrin, thus establishing a link between HJV-BMP and iron. 12 HJV exists in 2 forms: a membrane-bound (m-HJV) and a soluble one (s-HJV), which in vitro reciprocally regulate hepcidin expression in response to opposite iron changes. 7 s-HJV is able to interfere with and to block the signaling of BMP2 and BMP4 both in vitro 12 and in vivo. 13 We have previously documented the relevance of m-HJV in the molecular pathogenesis of juvenile hemochromatosis, providing evidence that at least some of the mutants identified as causal in patients are less efficiently targeted to the plasma membrane, compared with the wild-type protein. 9 Generation of s-HJV appears to be a regulated process decreased by iron treatment and diferric transferrin. 7 During our previous study, we have confirmed that this regulation is maintained in mutants, strengthening that s-HJV, suppressed by iron overload, is not involved in the disease pathogenesis. 9 We have also suggested that s-HJV does not derive from shedding of m-HJV, since its release in the medium is observed even in mutants that barely reach the plasma membrane. The discrepancy between the presence of m-HJV and the production of s-HJV is also well exemplified by the efficient secretion of soluble forms from varian...

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“…Nessas condições, embora a PiO 2 em condições de repouso no músculo esquelético seja de 1/5 da pressão de O 2 do ar inalado, o exercício agudo reduz a PiO 2 muscular na ordem de 1/40 23 . Assim, o aumento do HIF-1α no exercício agudo já estabelecido, coincide com a diminuição da expressão de pVHL 24 , revelando um importante papel do HIF em promover benefícios metabólicos para o desempenho físico em atletas 25 . A proteína quinase ativada por AMP (AMPK) é uma serina/treonina quinase que modula o metabolismo celular através da fosforilação de enzimas metabólicas ou via regulação transcricional 26 .…”

Section: Regulação Molecular Do Músculo Esquelético Ao Exercício Aeróunclassified

Adaptação Do Músculo Esquelético Ao Exercício Físico: Considerações Moleculares E Energéticas

Abreu

Leal-Cardoso

Ceccatto

2017

Rev Bras Med Esporte

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Artigo de revisãoReview ARticle ARtículo de Revisión RESUMOOs benefícios para a saúde e as adaptações fisiológicas ao exercício regular são amplamente conhecidos e, com o advento das ciências ômicas e moleculares, revelou-se uma complexa rede de vias de sinalização e moléculas reguladoras que coordenam a resposta adaptativa do músculo esquelético ao exercício. As mudanças orgânicas transientes, porém, são cumulativas no pós-exercício. Elas incluem, de forma principal, a transcrição de genes relacionados aos fatores regulatórios da miogênese, ao metabolismo de carboidratos, à mobilização de gorduras, ao transporte e oxidação de substratos, ao metabolismo mitocondrial através da fosforilação oxidativa e, por fim, à regulação transcricional de genes envolvidos na biogênese mitocondrial. Tendo em vista o grande impacto científico, resumiram-se neste trabalho, além de algumas das principais respostas moleculares sofridas pelo músculo esquelético com o exercício físico, fatores que coordenam a plasticidade muscular para o ganho de desempenho. Foram citadas dezenas de biomarcadores ligados a alguns aspectos moleculares das adaptações do músculo esquelético ao exercício físico, algumas principais vias sinalizadoras e o papel mitocondrial, revelando alguns novos paradigmas para o entendimento desta área científica.Descritores: exercício; músculo esquelético; biomarcadores; metabolismo energético. ABSTRACT

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Physiological activation of hypoxia inducible factor‐1 in human skeletal muscle

Cited by 222 publications

References 38 publications

PGC-1α is coupled to HIF-1α-dependent gene expression by increasing mitochondrial oxygen consumption in skeletal muscle cells

PGC-1α is coupled to HIF-1α-dependent gene expression by increasing mitochondrial oxygen consumption in skeletal muscle cells

Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis

Adaptação Do Músculo Esquelético Ao Exercício Físico: Considerações Moleculares E Energéticas

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