TY - JOUR
T1 - Eliminating the Ant1 isoform produces a mouse with CPEO pathology but normal ocular motility
AU - Yin, Hang
AU - Stahl, John S.
AU - Andrade, Francisco H.
AU - McMullen, Colleen A.
AU - Webb-Wood, Sarah
AU - Newman, Nancy J.
AU - Biousse, Valerie
AU - Wallace, Douglas C.
AU - Pardue, Machelle T.
PY - 2005/12
Y1 - 2005/12
N2 - PURPOSE. The adenine nucleotide transporter 1 gene (ANT1) encodes an inner mitochondrial membrane protein that transports ATP into the cell. Mutations within ANT1 produce a syndrome of chronic progressive external ophthalmoplegia (CPEO) in humans. Ant1 knockout (Ant1-/-) mice develop cardiomyopathy and mitochondrial myopathy of limb muscles. Because the extraocular muscles (EOM) are preferentially affected in human CPEO, the objective of this study was to determine whether Ant1-/- mice also exhibit an EOM mitochondrial myopathy. METHODS. ANT isoform expression of isolated EOMs, EOM morphology and mitochondrial content, mitochondrial structure and function, ocular motility in intact mice, and contractile performance in isolated muscle preparations were examined. RESULTS. Ant1-/- EOMs had the typical appearance of mitochondrial myopathy, including increase in mitochondrial size, number, and oxidative phosphoiylation (OXPHOS) staining. However, there were no measurable ocular motor abnormalities in intact Ant1-/- mice, and their isolated EOMs did not show evidence of increased fatigability. EOMs of wild-type mice exhibited higher levels of Ant2 mRNA compared with hindlimb muscle, which may compensate for the Ant1 loss in mutant mouse EOMs and account for the normal EOM function. CONCLUSIONS. The Ant1-/- mice provide a model in which to study CPEO pathology and compensatory mechanisms.
AB - PURPOSE. The adenine nucleotide transporter 1 gene (ANT1) encodes an inner mitochondrial membrane protein that transports ATP into the cell. Mutations within ANT1 produce a syndrome of chronic progressive external ophthalmoplegia (CPEO) in humans. Ant1 knockout (Ant1-/-) mice develop cardiomyopathy and mitochondrial myopathy of limb muscles. Because the extraocular muscles (EOM) are preferentially affected in human CPEO, the objective of this study was to determine whether Ant1-/- mice also exhibit an EOM mitochondrial myopathy. METHODS. ANT isoform expression of isolated EOMs, EOM morphology and mitochondrial content, mitochondrial structure and function, ocular motility in intact mice, and contractile performance in isolated muscle preparations were examined. RESULTS. Ant1-/- EOMs had the typical appearance of mitochondrial myopathy, including increase in mitochondrial size, number, and oxidative phosphoiylation (OXPHOS) staining. However, there were no measurable ocular motor abnormalities in intact Ant1-/- mice, and their isolated EOMs did not show evidence of increased fatigability. EOMs of wild-type mice exhibited higher levels of Ant2 mRNA compared with hindlimb muscle, which may compensate for the Ant1 loss in mutant mouse EOMs and account for the normal EOM function. CONCLUSIONS. The Ant1-/- mice provide a model in which to study CPEO pathology and compensatory mechanisms.
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U2 - 10.1167/iovs.05-0695
DO - 10.1167/iovs.05-0695
M3 - Article
C2 - 16303948
AN - SCOPUS:33644807657
SN - 0146-0404
VL - 46
SP - 4555
EP - 4562
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
IS - 12
ER -