Human mitochondrial transcription factor A reduction and mitochondrial dysfunction in Hashimoto's hypothyroid myopathy.
BACKGROUND
Mitochondrial changes have been described in muscle tissue in acquired hypothyroidism. Among the molecular mechanisms by which thyroid hormones regulate expression of nuclear genes encoding for regulatory proteins of mitochondrial respiratory function, the mitochondrial transcription factor A (h-mtTFA) has been proposed to be a target of thyroid hormone action. The aim of this study has been to relate h-mtTFA levels in the skeletal muscle of patients affected by Hashimoto's hypothyroidism and myopathy (HHM) to muscle disease and thyroid status.


METHODS
Eleven HHM patients underwent complete thyroid status and neurologic assessment, along with determination of exercise lactate anaerobic threshold (LT) and muscle biopsy in which h-mtTFA levels were measured and mtDNA was analyzed.


RESULTS
Decreased exercise lactate threshold, presence of cytochrome c oxidase negative fibers, reduction of cytochrome c oxidase activity, and mitochondrial DNA copy number at muscle biopsy were indicative of mitochondrial involvement in these patients. Furthermore, muscle h-mtTFA levels were reduced to a variable extent in comparison with a group of euthyroid controls. The h-mtTFA levels were inversely correlated with TSH and LT lactate, and positively correlated with FT4.


CONCLUSIONS
These results indicate that low levels of the h-mtTFA occur in skeletal muscle of HHM and suggest that abnormal h-mtTFA turnover may be implicated in the pathogenesis of mitochondrial alterations in this disease.
Siciliano
Gabriele
G
Department of Neuroscience, University of Pisa, Italy. gsicilia@neuro.med.unipi.it
Monzani
Fabio
F
Manca
Maria Laura
ML
Tessa
Alessandra
A
Caraccio
Nadia
N
Tozzi
Giulia
G
Piemonte
Fiorella
F
Mancuso
Michelangelo
M
Santorelli
Filippo Maria
FM
Ferrannini
Eleuterio
E
Murri
Luigi
L
D001706:Biopsy; D004268:DNA-Binding Proteins; D004576:Electromyography; D005260:Female; D006801:Humans; D019344:Lactic Acid / Q000097:blood; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins; D018482:Muscle, Skeletal / Q000378:metabolism / Q000601:surgery; D009687:Nuclear Proteins / Q000378:metabolism*; D013961:Thyroid Gland / Q000378:metabolism; D013967:Thyroiditis, Autoimmune / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; C499631:TFAM protein, human; D014157:Transcription Factors; C422562:mitochondrial transcription factor A; D019344:Lactic Acid