Analysis Tools
growth/size/body
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• mice have grossly enlarged hearts at 9 weeks of age
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• 9-week old mice show significant increase in heart weight/tibial-length ratios
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weight loss
(
J:113016
)
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• male mutants appear normal at 2 months; at 3 months, they display significant weight loss
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cellular
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• mitochondria display abnormal morphology at 9 weeks but not at 4 weeks of age
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• mitochondria display marked cristolysis at 9 weeks but not at 4 weeks of age
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• heart muscle has increased number of mitochondria
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• lipid peroxidation markers are increased >2.5 fold in 9-week old mutants indicating impaired mitochondrial respiration
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• a significant increase in lactate/pyruvate ratio is observed
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• complex I respiratory chain complex is reduced to ~50% of control levels in heart and gastrocnemius at 5 weeks of age, while complex III level is ~90% of control in heart and gastrocnemius
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• respiratory chain enzyme activities in soleus, gastrocnemium and heart muscle is severely reduced; complex I activity in skeletal muscle and heart is reduced (up to 80%) while complex IV activity in the heart is more mildly reduced at 18 weeks of age
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• lipid peroxidation markers (indicators or oxidative stress) are increased >2.5 fold in 9-week old mutants
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cardiovascular system
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• heart muscle shows pronounced myofibrillar fragmentation and disorganization and increased number of mitochondria
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• individual cardiomyocytes are markedly increased in size
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• mice have grossly enlarged hearts at 9 weeks of age
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• 9-week old mice show significant increase in heart weight/tibial-length ratios
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• mutants display severe dilated cardiomyopathy
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• detectable by 4 weeks of age and progressively worsens
• significant decrease is shown by decreased percentage fractional shortening, decreased velocity of circumferential fiber shortening and reduced peak aortic outlflow velocity
• also, dP/dTmax and dP/dTmin are reduced significantly
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• mutants have significant decrease in ventricular blood pressures
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muscle
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• heart muscle shows pronounced myofibrillar fragmentation and disorganization and increased number of mitochondria
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• individual cardiomyocytes are markedly increased in size
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• mutants display severe dilated cardiomyopathy
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• detectable by 4 weeks of age and progressively worsens
• significant decrease is shown by decreased percentage fractional shortening, decreased velocity of circumferential fiber shortening and reduced peak aortic outlflow velocity
• also, dP/dTmax and dP/dTmin are reduced significantly
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• myofibers from 3-month old mice display irregular contours
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• myofiber cross-sectional area is reduced 2-fold in triceps of 3 month old mice vs littermate controls
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• male hemizygotes display significant loss of muscle mass at 3 months, becoming detectable at 10 weeks of age compared to littermate controls (Pdcd8-sufficent and non-transgenic hemizygotes)
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• muscle degeneration is progressive, becoming detectable at 10 weeks of age; it is most apparent in fast-twitch muscles (gastrocnemium, triceps, quadriceps)
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• all skeletal muscles analyzed including triceps, pectoralis, quadriceps, gluteus, and gastrocnemius muscles are significantly atrophied male hemizygotes
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homeostasis/metabolism
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• plasma lactate levels increase progressively with muscle loss
• a significant increase in lactate/pyruvate ratio is observed
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• mutant cardiomyocytes undergo compensatory metabolic switch toward glycolysis, and away from pyruvate utilization as result of impaired mitochondrial respiration
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• mutants show significant upregulation of atrial naturietic factor (ANF) and b-type natruietic peptide (BNP)
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• at 4.5 months of age, heart and skeletal muscle show significant reductions in catalase activity
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behavior/neurological
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• loss of muscle mass results makes mice extremely lethargic by 5 months of age
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