TY - JOUR
T1 - Novel role of Tieg1 in muscle metabolism and mitochondrial oxidative capacities
AU - Kammoun, Malek
AU - Piquereau, Jerome
AU - Nadal-Desbarats, Lydie
AU - Même, Sandra
AU - Beuvin, Maud
AU - Bonne, Gisèle
AU - Veksler, Vladimir
AU - Le Fur, Yann
AU - Pouletaut, Philippe
AU - Même, William
AU - Szeremeta, Frederic
AU - Constans, Jean Marc
AU - Bruinsma, Elizabeth S.
AU - Nelson Holte, Molly H.
AU - Najafova, Zeynab
AU - Johnsen, Steven A.
AU - Subramaniam, Malayannan
AU - Hawse, John R.
AU - Bensamoun, Sabine F.
N1 - Publisher Copyright:
© 2019 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd
PY - 2020/3/1
Y1 - 2020/3/1
N2 - 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.
AB - 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.
KW - Klf10
KW - Tieg1
KW - metabolism
KW - mitochondria
KW - skeletal muscle
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U2 - 10.1111/apha.13394
DO - 10.1111/apha.13394
M3 - Article
C2 - 31560161
AN - SCOPUS:85074283922
SN - 1748-1708
VL - 228
JO - Acta Physiologica
JF - Acta Physiologica
IS - 3
M1 - e13394
ER -