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Aging, The Molecular Concepts

2.9. ANT1-DEFICIENT MICE

The mouse has two ANT isoforms: the heart-muscle isoform (ANT1) located on chromosome 8 adjacent to the D8MitS locus (83) and the systemic isoform (ANT2) expressed in all tissues but skeletal muscle and located on the X chromosome (84). ANT1 was expressed strongly in heart and muscle and weaklier in brain. ANT2 was expressed in all tissues but skeletal muscle.

Physiological analyses of the ANT1 -/- animals revealed that they had a lactic acidosis with a 4.2 fold increase in lactate over controls. They also showed a 1.55-fold increase in alanine, a 1.73- fold increase in citrate and a 48- fold increase in succinate. Hence, the ANT1 mice have a similar physiological profile as patients with mitochondrial myopathy and cardiomyopathy.

Pathological analyses of the ANT1 -/- mice confirmed the presence of mitochondrial myopathy and cardiomyopathv. Analysis of frozen sections revealed that ANT1 -/- animals at 6 months of age had classic RRF. Moreover staining with COX and SDH revealed a marked increase in mitochondrial staining in the Type I oxidative fibers in ANT1 -/- animals relative to controls. Finally ultrastructural analysis revealed that the ANT1 -/- muscle showed a marked disintegration of the contractible elements and a massive proliferation of giant, swollen mitochondria. Indeed, some muscle fibers are virtually filled with mitochondria. Analysis of the hearts of 4-6 months ANT1 -/- mice revealed a classic hypertrophic cardiomyopathy. The mean heart weight of ANT1 -/- animals was 7.23 ± 0.86 mg/g body weight while that for ANT1 +/+ animals was 4.67 ± 0.77 mg/g body weight a 1.55- fold increase. Ultrastructural analysis also revealed a partial reduction in contractile elements and a substantial induction of mitochondria proliferation. Finally ANT1 -/- and ANT1 +/+ animals were subjected to an exercise stress test using an enclosed treadmill with flow-through monitors of CO2 and O2 levels (Columbus Instruments. Columbus. OH). This revealed that the ANT1 -/- mice were highly fatiguable, collapsing after half the exercise regimen of the ANT1 +/+ animals. Moreover, they showed a marked difference in O2 consumption and CO2 exhalation relative to controls during graded exercise (83). These observations demonstrate that the ANT1 -/- mouse exhibits all of the phenotypic, metabolic and biochemical features that we see in human patients with mitochondrial myopathy and hypertrophic cardiomyopathy. Thus, these data provide the first direct cause-and-effect proof that limitation of mitochondrial energy production can cause the kinds of age-related degenerative symptoms that we see in mitochondrial disease patients and in aging.

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