Novel role of Tieg1 in muscle metabolism and mitochondrial oxidative capacities

Aim Tieg1 is involved in multiple signalling pathways, human diseases, and is highly expressed in muscle where its functions are poorly understood. Methods We have utilized Tieg1 knockout (KO) mice to identify novel and important roles for this transcription factor in regulating muscle ultrastructur...

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Published in:Acta Physiologica 2020-03, Vol.228 (3), p.e13394-n/a
Main Authors: Kammoun, Malek, Piquereau, Jerome, Nadal‐Desbarats, Lydie, Même, Sandra, Beuvin, Maud, Bonne, Gisèle, Veksler, Vladimir, Le Fur, Yann, Pouletaut, Philippe, Même, William, Szeremeta, Frederic, Constans, Jean‐Marc, Bruinsma, Elizabeth S., Nelson Holte, Molly H., Najafova, Zeynab, Johnsen, Steven A., Subramaniam, Malayannan, Hawse, John R., Bensamoun, Sabine F.
Format: Article
Language:English
Subjects:
Biochemistry, Molecular Biology
Citrate synthase
Cytochrome-c oxidase
Electron transport chain
Enzymatic activity
Gene expression
Human health and pathology
Immunoblotting
Intolerance
Klf10
Life Sciences
Magnetic resonance imaging
Metabolism
Mitochondria
Muscles
NMR
Nuclear magnetic resonance
Oxidative metabolism
Phenotypes
Phosphocreatine
Ribonucleic acid
RNA
Signal transduction
Skeletal muscle
Soleus muscle
Succinate dehydrogenase
Tieg1
Tissues and Organs
Transmission electron microscopy
Ultrastructure
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Summary:Aim Tieg1 is involved in multiple signalling pathways, human diseases, and is highly expressed in muscle where its functions are poorly understood. Methods We have utilized Tieg1 knockout (KO) mice to identify novel and important roles for this transcription factor in regulating muscle ultrastructure, metabolism and mitochondrial functions in the soleus and extensor digitorum longus (EDL) muscles. RNA sequencing, immunoblotting, transmission electron microscopy, MRI, NMR, histochemical and mitochondrial function assays were performed. Results Loss of Tieg1 expression resulted in altered sarcomere organization and a significant decrease in mitochondrial number. Histochemical analyses demonstrated an absence of succinate dehydrogenase staining and a decrease in cytochrome c oxidase (COX) enzyme activity in KO soleus with similar, but diminished, effects in the EDL. Decreased complex I, COX and citrate synthase (CS) activities were detected in the soleus muscle of KO mice indicating altered mitochondrial function. Complex I activity was also diminished in KO EDL. Significant decreases in CS and respiratory chain complex activities were identified in KO soleus. 1H‐NMR spectra revealed no significant metabolic difference between wild‐type and KO muscles. However, 31P spectra revealed a significant decrease in phosphocreatine and ATPγ. Altered expression of 279 genes, many of which play roles in mitochondrial and muscle function, were identified in KO soleus muscle. Ultimately, all of these changes resulted in an exercise intolerance phenotype in Tieg1 KO mice. Conclusion Our findings have implicated novel roles for Tieg1 in muscle including regulation of gene expression, metabolic activity and organization of tissue ultrastructure. This muscle phenotype resembles diseases associated with exercise intolerance and myopathies of unknown consequence.
ISSN:1748-1708
1748-1716
DOI:10.1111/apha.13394