Skeletal muscle overexpression of nuclear respiratory factor 1 increases glucose transport capacity.
Nuclear respiratory factor 1 (NRF-1) is a transcriptional activator of nuclear genes that encode a range of mitochondrial proteins including cytochrome c, various other respiratory chain subunits, and delta-aminolevulinate synthase. Activation of NRF-1 in fibroblasts has been shown to induce increases in cytochrome c expression and mitochondrial respiratory capacity. To further evaluate the role of NRF-1 in the regulation of mitochondrial biogenesis and respiratory capacity, we generated transgenic mice overexpressing NRF-1 in skeletal muscle. Cytochrome c expression was increased approximately twofold and delta-aminolevulinate synthase was increased approximately 50% in NRF-1 transgenic muscle. The levels of some mitochondrial proteins were increased 50-60%, while others were unchanged. Muscle respiratory capacity was not increased in the NRF-1 transgenic mice. A finding that provides new insight regarding the role of NRF-1 was that expression of MEF2A and GLUT4 was increased in NRF-1 transgenic muscle. The increase in GLUT4 was associated with a proportional increase in insulin-stimulated glucose transport. These results show that an isolated increase in NRF-1 is not sufficient to bring about a coordinated increase in expression of all of the proteins necessary for assembly of functional mitochondria. They also provide the new information that NRF-1 overexpression results in increased expression of GLUT4.
Baar
Keith
K
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Song
Zheng
Z
Semenkovich
Clay F
CF
Jones
Terry E
TE
Han
Dong-Ho
DH
Nolte
Lorraine A
LA
Ojuka
Edward O
EO
Chen
May
M
Holloszy
John O
JO
D000818:Animals; D001692:Biological Transport; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000201:enzymology; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D018006:Myogenic Regulatory Factors; D051265:NF-E2-Related Factor 1; D051266:Nuclear Respiratory Factor 1; D051264:Nuclear Respiratory Factors; D010084:Oxidation-Reduction; D019289:Pyruvic Acid / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; C578036:Mef2a protein, mouse; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D018006:Myogenic Regulatory Factors; D051265:NF-E2-Related Factor 1; C495633:NRF1 protein, human; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D051264:Nuclear Respiratory Factors; C495692:SLC2A4 protein, human; C495693:Slc2a4 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D019289:Pyruvic Acid; D005947:Glucose