Increased expression of mitochondrial transcription factor A and nuclear respiratory factor-1 in skeletal muscle from aged human subjects

Mitochondrial transcription factor A (Tfam) is a nuclear-encoded gene product that is imported into mitochondria and is required for the transcription of mitochondrial DNA (mtDNA). We hypothesized that conditions known to produce mitochondrial biogenesis in skeletal muscle would be preceded by an increase in Tfam expression. Therefore, rat muscle was stimulated (10 Hz, 3 h/day). Tfam mRNA levels were significantly elevated (by 55%) at 4 days and returned to control levels at 14 days. Tfam import into intermyofibrillar (IMF) mitochondria was increased by 52 and 61% ( P < 0.05) at 5 and 7 days, respectively. This corresponded to an increase in the level of import machinery components. Immunoblotting data indicated that IMF Tfam protein content was increased by 63% ( P < 0.05) at 7 days of stimulation. This was associated with a 49% ( P < 0.05) increase in complex formation at the mtDNA promoter and a 65% ( P< 0.05) increase in the levels of a mitochondrial transcript, cytochrome- c oxidase (COX) subunit III. Similarly, COX enzyme activity was elevated by 71% ( P < 0.05) after 7 days of contractile activity. These results indicate that early events in mitochondrial biogenesis include increases in Tfam mRNA, followed by accelerations in mitochondrial import and increased Tfam content, which correspond with increased binding to the mtDNA promoter region. This was accompanied by increased mitochondrial transcript levels and elevated COX activity. These data support the role of Tfam as a regulatory protein involved in contractile activity-induced mitochondrial biogenesis.

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Zidovudine (AZT) induced alterations in mitochondrial biogenesis in rat striated muscles

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y98-151 ◽

1999 ◽

Vol 77 (1) ◽

pp. 29-35 ◽

Cited By ~ 7

Author(s):

Damien Freyssenet ◽

Martino DiCarlo ◽

Patricia Escobar ◽

Janice Grey ◽

Jeremy Schneider ◽

...

Keyword(s):

Blood Pressure ◽

Skeletal Muscle ◽

Transcription Factor ◽

Enzyme Activity ◽

Muscle Performance ◽

Mitochondrial Transcription ◽

Mitochondrial Transcription Factor ◽

Mitochondrial Defects ◽

Mitochondrial Transcription Factor A ◽

Skeletal Muscle Performance

Zidovudine (AZT) and didanosine (ddI), two drugs used in the treatment of AIDS, are also known to cause mitochondrial abnormalities. We investigated the physiological relevance of the mitochondrial defects by measuring in situ skeletal muscle performance and cytochrome c oxidase (CYTOX) enzyme activity in heart muscle, red high-oxidative (RG) and white low-oxidative (WG) portions of the gastrocnemius muscle of control (n = 17), AZT- (n = 14), or ddI-treated (n = 11) rats for 28 days. We also evaluated the hypothesis that AZT treatment could alter the expression of the mitochondrial transcription factor A (mtTFA), a key molecule involved in mitochondrial DNA (mtDNA) replication and transcription. AZT had a pronounced effect on blood pressure and skeletal muscle performance, which were significantly decreased during contractile activity at 2 and 5 Hz, compared with control. A significant decrease in CYTOX activity in heart and RG, but not WG muscles, was also evident. In the heart, this was accompanied by an apparent compensatory increase in mtTFA mRNA level that could not be attributed to enhanced transcriptional activation mediated by nuclear respiratory factor 1 (NRF-1). In contrast with AZT, no effect of ddI was found on the extent of fatigue or muscle enzyme activity. These results indicate that AZT induces mitochondrial defects primarily in muscles with the highest oxidative capacities (heart and RG). The long-term effects of AZT on mitochondrial biogenesis have the potential to reduce muscle performance, but the effects on performance in this short-term study were likely due to an inability of the AZT-treated animals to maintain blood pressure during contractile activity.Key words: mitochondrial myopathy, endurance performance, cytochrome c oxidase, mitochondrial transcription factor A, zidovudine, didanosine.

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MicroRNA-494 regulates mitochondrial biogenesis in skeletal muscle through mitochondrial transcription factor A and Forkhead box j3

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00097.2012 ◽

2012 ◽

Vol 303 (12) ◽

pp. E1419-E1427 ◽

Cited By ~ 82

Author(s):

Hirotaka Yamamoto ◽

Katsutaro Morino ◽

Yoshihiko Nishio ◽

Satoshi Ugi ◽

Takeshi Yoshizaki ◽

...

Keyword(s):

Skeletal Muscle ◽

Transcription Factor ◽

Mitochondrial Biogenesis ◽

Target Genes ◽

Myogenic Differentiation ◽

Muscle Adaptation ◽

Mitochondrial Transcription ◽

Mitochondrial Transcription Factor ◽

Forkhead Box ◽

Mitochondrial Transcription Factor A

MicroRNAs (miRNAs) are important posttranscriptional regulators of various biological pathways. In this study, we focused on the role of miRNAs during mitochondrial biogenesis in skeletal muscle. The expression of miR-494 was markedly decreased in murine myoblast C2C12 cells during myogenic differentiation, accompanied by an increase in mtDNA. Furthermore, the expression of predicted target genes for miR-494, including mitochondrial transcription factor A (mtTFA) and Forkhead box j3 (Foxj3), was posttranscriptionally increased during myogenic differentiation. Knockdown of miR-494 resulted in increased mitochondrial content and upregulation of mtTFA and Foxj3 at the protein level. A 3′-untranslated region reporter assay revealed that miR-494 knockdown directly upregulated the luciferase activity of mtTFA and Foxj3. All of these observations were reversed by overexpression of miR-494. Furthermore, the miR-494 content significantly decreased after endurance exercise in C57BL/6J mice, accompanied by an increase in expression of mtTFA and Foxj3 proteins. These results suggest that miR-494 regulates mitochondrial biogenesis by downregulating mtTFA and Foxj3 during myocyte differentiation and skeletal muscle adaptation to physical exercise.

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The regulation of mitochondrial transcription factor A (Tfam) expression during skeletal muscle cell differentiation

Bioscience Reports ◽

10.1042/bsr20150073 ◽

2015 ◽

Vol 35 (3) ◽

Cited By ~ 19

Author(s):

Melania Collu-Marchese ◽

Michael Shuen ◽

Marion Pauly ◽

Ayesha Saleem ◽

David A. Hood

Keyword(s):

Skeletal Muscle ◽

Transcription Factor ◽

Skeletal Muscle Cell ◽

Mitochondrial Content ◽

Mitochondrial Transcription ◽

Muscle Cell Differentiation ◽

Mitochondrial Transcription Factor ◽

Mitochondrial Transcription Factor A ◽

Post Transcriptional Regulation ◽

The Relationship

The present study highlights the transcriptional and post-transcriptional regulation of mitochondrial transcription factor A (Tfam) during myogenesis and the relationship this has with the increase in mitochondrial content during differentiation.

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