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Potential mechanisms of muscle mitochondrial dysfunction in aging and obesity and cellular consequences.

Chanséaume E, Morio B - Int J Mol Sci (2009)

Bottom Line: Mitochondria play a key role in the energy metabolism in skeletal muscle.According to current knowledge, the causes and the underlying molecular mechanisms at the origin of decreased mitochondrial oxidative capacity in skeletal muscle still remain to be elucidated.The present review focuses on recent data investigating these issues in the area of metabolic disorders and describes the potential causes, mechanisms and consequences of mitochondrial dysfunction in the skeletal muscle.

View Article: PubMed Central - PubMed

Affiliation: INRA, UMR Nutrition Humaine, Saint Genès Champanelle, France. emilie@nutrifizz.fr

ABSTRACT
Mitochondria play a key role in the energy metabolism in skeletal muscle. A new concept has emerged suggesting that impaired mitochondrial oxidative capacity in skeletal muscle may be the underlying defect that causes insulin resistance. According to current knowledge, the causes and the underlying molecular mechanisms at the origin of decreased mitochondrial oxidative capacity in skeletal muscle still remain to be elucidated. The present review focuses on recent data investigating these issues in the area of metabolic disorders and describes the potential causes, mechanisms and consequences of mitochondrial dysfunction in the skeletal muscle.

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Related in: MedlinePlus

Major transcription factors involved in the regulation of muscle mitochondrial oxidative and phosphorylation (OXPHOS) activity. Non exhaustive key genes, whose expression is regulated by the transcription factors, are given for example.
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f1-ijms-10-00306: Major transcription factors involved in the regulation of muscle mitochondrial oxidative and phosphorylation (OXPHOS) activity. Non exhaustive key genes, whose expression is regulated by the transcription factors, are given for example.

Mentions: Muscle oxidative capacity is mainly determined by the mitochondrial density that depends on mitochondrial biogenesis (i.e. the cellular processes involved in the synthesis of the organelles), and the mitochondrial oxidative capacity, which relies on the oxidative enzyme content and activity. A number of transcriptional modulators have been implicated in the regulation of muscle mitochondrial biogenesis and OXPHOS activity. They include PPAR gamma coactivator 1 alpha (PGC-1α), in cooperation with several factors such as the peroxisome proliferator-activated receptors (PPAR), the nuclear respiratory factors 1 and 2 (NRF-1 and NRF-2) [1–9], or the specificity protein 1 (Sp1), an ubiquitous transcription factor known to regulate the constitutive expression of oxidative OXPHOS genes [10]. Of note, Sp1 can function as both a positive (e.g. cytochrome c1 and mitochondrial transcription factor A, TFAM) and a negative (e.g. adenine nucleotide translocator 2 and F1-ATPase beta subunit) regulator of transcription [11]. PGC-1α is a master modulator of gene expression in skeletal muscle [12]. It was found to drive the formation of oxidative type I fibres and to activate the expression of genes involved in mitochondrial oxidative capacity, through associated changes in the expression of NRF dependent genes [13]. These combined data have therefore suggested that decreased PGC-1α gene expression could be one of the primary contributors to decreased mitochondrial oxidative capacity. However, PPARs are also good candidates. When bound to their ligand (e.g. fatty acids for PPARα), PPARs form a heterodimeric complex with the retinoid X receptor (RXR) to regulate gene transcription involved in fatty acid metabolism. PGC-1α is also known to enhance the activity of the isoforms PPARα and PPARβ/δ in skeletal muscle, which may result in the enhanced expression of genes involved in mitochondrial fatty acid oxidation [14]. Major transcriptional modulators involved in the regulation of mitochondrial activity in skeletal muscle are illustrated in Figure 1 (see also [14–16] for reviews). All factors mentioned above co-regulate the transcriptional activity of a variety of genes involved in mitochondrial biogenesis, OXPHOS activity and fatty acid oxidation. For example, in muscle cells, overexpression of PGC-1α was shown to induce the gene expression of NRF-1, NRF-2, TFAM and mitochondrial-encoded cytochrome c oxidase (COX) subunits [15]. Likewise, muscle–specific overexpression of PPARβ/δ in mice was shown to increase oxidative enzyme activities such as citrate synthase or b-hydroxyacyl-CoA dehydrogenase, and to enhance expression of genes implicated in fatty acid catabolism [17].


Potential mechanisms of muscle mitochondrial dysfunction in aging and obesity and cellular consequences.

Chanséaume E, Morio B - Int J Mol Sci (2009)

Major transcription factors involved in the regulation of muscle mitochondrial oxidative and phosphorylation (OXPHOS) activity. Non exhaustive key genes, whose expression is regulated by the transcription factors, are given for example.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2662471&req=5

f1-ijms-10-00306: Major transcription factors involved in the regulation of muscle mitochondrial oxidative and phosphorylation (OXPHOS) activity. Non exhaustive key genes, whose expression is regulated by the transcription factors, are given for example.
Mentions: Muscle oxidative capacity is mainly determined by the mitochondrial density that depends on mitochondrial biogenesis (i.e. the cellular processes involved in the synthesis of the organelles), and the mitochondrial oxidative capacity, which relies on the oxidative enzyme content and activity. A number of transcriptional modulators have been implicated in the regulation of muscle mitochondrial biogenesis and OXPHOS activity. They include PPAR gamma coactivator 1 alpha (PGC-1α), in cooperation with several factors such as the peroxisome proliferator-activated receptors (PPAR), the nuclear respiratory factors 1 and 2 (NRF-1 and NRF-2) [1–9], or the specificity protein 1 (Sp1), an ubiquitous transcription factor known to regulate the constitutive expression of oxidative OXPHOS genes [10]. Of note, Sp1 can function as both a positive (e.g. cytochrome c1 and mitochondrial transcription factor A, TFAM) and a negative (e.g. adenine nucleotide translocator 2 and F1-ATPase beta subunit) regulator of transcription [11]. PGC-1α is a master modulator of gene expression in skeletal muscle [12]. It was found to drive the formation of oxidative type I fibres and to activate the expression of genes involved in mitochondrial oxidative capacity, through associated changes in the expression of NRF dependent genes [13]. These combined data have therefore suggested that decreased PGC-1α gene expression could be one of the primary contributors to decreased mitochondrial oxidative capacity. However, PPARs are also good candidates. When bound to their ligand (e.g. fatty acids for PPARα), PPARs form a heterodimeric complex with the retinoid X receptor (RXR) to regulate gene transcription involved in fatty acid metabolism. PGC-1α is also known to enhance the activity of the isoforms PPARα and PPARβ/δ in skeletal muscle, which may result in the enhanced expression of genes involved in mitochondrial fatty acid oxidation [14]. Major transcriptional modulators involved in the regulation of mitochondrial activity in skeletal muscle are illustrated in Figure 1 (see also [14–16] for reviews). All factors mentioned above co-regulate the transcriptional activity of a variety of genes involved in mitochondrial biogenesis, OXPHOS activity and fatty acid oxidation. For example, in muscle cells, overexpression of PGC-1α was shown to induce the gene expression of NRF-1, NRF-2, TFAM and mitochondrial-encoded cytochrome c oxidase (COX) subunits [15]. Likewise, muscle–specific overexpression of PPARβ/δ in mice was shown to increase oxidative enzyme activities such as citrate synthase or b-hydroxyacyl-CoA dehydrogenase, and to enhance expression of genes implicated in fatty acid catabolism [17].

Bottom Line: Mitochondria play a key role in the energy metabolism in skeletal muscle.According to current knowledge, the causes and the underlying molecular mechanisms at the origin of decreased mitochondrial oxidative capacity in skeletal muscle still remain to be elucidated.The present review focuses on recent data investigating these issues in the area of metabolic disorders and describes the potential causes, mechanisms and consequences of mitochondrial dysfunction in the skeletal muscle.

View Article: PubMed Central - PubMed

Affiliation: INRA, UMR Nutrition Humaine, Saint Genès Champanelle, France. emilie@nutrifizz.fr

ABSTRACT
Mitochondria play a key role in the energy metabolism in skeletal muscle. A new concept has emerged suggesting that impaired mitochondrial oxidative capacity in skeletal muscle may be the underlying defect that causes insulin resistance. According to current knowledge, the causes and the underlying molecular mechanisms at the origin of decreased mitochondrial oxidative capacity in skeletal muscle still remain to be elucidated. The present review focuses on recent data investigating these issues in the area of metabolic disorders and describes the potential causes, mechanisms and consequences of mitochondrial dysfunction in the skeletal muscle.

Show MeSH
Related in: MedlinePlus