Analysis Tools
mortality/aging
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• ~30% of mice die by 12 weeks of age
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cardiovascular system
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• mice exhibit signs of cardiomyocyte mineralization starting from 6 weeks of age
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• TEM analysis of 16-week-old hearts shows signs of hypercondensed and disorganized cristae in both interfibrillar and perinuclear mitochondria, suggesting mitochondrial dysfunction
• however, no swelling or significant changes in mitochondrial size or cross-sectional area are observed
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• mice show a significant increase in relative amount of mtDNA in heart muscle
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• mice show clear signs of cardiomyocyte hypertrophy at 8 and 12 weeks of age
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• mice exhibit signs of cardiomyocyte vacuolation starting from 6 weeks of age
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• mice exhibit cardiomyocyte disorganization starting from 6 weeks of age
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• at 12 weeks of age, both absolute heart weight and heart weight normalized to femur length is significantly higher than in wild-type controls
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• at 12 weeks of age, mice show a significant increase in left ventricular (LV) volume
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• at 12 weeks of age, mice show a significant increase in left ventricular (LV) mass
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• at 12 weeks of age
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• at 12 weeks of age
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• at 12 weeks of age, M-mode echocardiography shows a significant increase in LV mass and volume and marked reductions in stroke volume, % ejection fraction, heart rate, and cardiac output
• however, ECG parameters are relatively normal
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• mice exhibit progressive hypertrophic cardiomyopathy (HCM) starting from 6 weeks of age
• however, no other severe muscular phenotypes are observed
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muscle
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• mice exhibit signs of cardiomyocyte mineralization starting from 6 weeks of age
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• TEM analysis of 16-week-old hearts shows signs of hypercondensed and disorganized cristae in both interfibrillar and perinuclear mitochondria, suggesting mitochondrial dysfunction
• however, no swelling or significant changes in mitochondrial size or cross-sectional area are observed
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• mice show a significant increase in relative amount of mtDNA in heart muscle
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• mice show clear signs of cardiomyocyte hypertrophy at 8 and 12 weeks of age
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• mice exhibit signs of cardiomyocyte vacuolation starting from 6 weeks of age
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• mice exhibit cardiomyocyte disorganization starting from 6 weeks of age
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• mice exhibit progressive hypertrophic cardiomyopathy (HCM) starting from 6 weeks of age
• however, no other severe muscular phenotypes are observed
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• in the presence of pyruvate and malate, isolated heart mitochondria show a significant reduction in State III and State IIIu oxygen consumption levels
• however, brain mitochondria show no significant change in the oxygen consumption rate
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• at 12 weeks of age, the cross-sectional area of both the soleus and extensor digitorum longus (EDL) muscles is significantly decreased with no detectable change in myosin heavy chain fiber types
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cellular
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• TEM analysis of 16-week-old hearts shows signs of hypercondensed and disorganized cristae in both interfibrillar and perinuclear mitochondria, suggesting mitochondrial dysfunction
• however, no swelling or significant changes in mitochondrial size or cross-sectional area are observed
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• mice show a significant increase in relative amount of mtDNA in heart muscle
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• 16-week-old hearts show signs of hypercondensed and disorganized cristae in both interfibrillar and perinuclear mitochondria
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• in the presence of pyruvate and malate, isolated heart mitochondria show a significant reduction in State III and State IIIu oxygen consumption levels
• however, brain mitochondria show no significant change in the oxygen consumption rate
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• mice show a significant reduction in both MFN2 and OPA1 (mitochondrial fusion proteins) and a significant increase in the PINK1 degradation protein, suggesting a tendency towards increased mitochondrial turnover and altered overall mitochondrial dynamics
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• whole-heart lysates from 16-week-old mice show a 98% reduction of complex I (NDUFB8) protein levels in the heart, with no significant change in any other cardiac electron transport chain (ETC) protein levels
• at 16 weeks of age, complex I protein levels are also reduced in brain (~30%), kidney (~30%), and liver (~60%), but not in skeletal muscle
• complex I in gel activity is significantly decreased in cardiac mitochondria and slightly reduced in liver mitochondria but not significantly altered in brain mitochondria
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• PPARGC1A, the master regulator of mitochondrial biogenesis, is significantly reduced at both the mRNA (20%) and protein level (29.5%) in the heart
• at 16 weeks of age, quantification of cardiac complex I protein abundance of various proteins representing complex I subunits and accessory proteins shows a significant reduction in the levels of all tested proteins except two proteins (NDUFS3 and MT-ND1); all proteins in each of the subassemblies of complex I (N-NDUFV2, Q-NDUFS2, Pp-NDUFC2, PD-NDUFB11, NDUFB8) show loss of mRNA expression as well as a decrease in protein abundance
• mitochondrial complex I protein NDUFB8 is significantly reduced as early as 2 weeks of age, while other mitochondrial proteins are unchanged
• BN-PAGE blots show that some aspects of complex I assembly are impaired in cardiac tissue; defects mainly relate to the assembly of the membrane arm of Complex I, although loss of other subunits is also noted
• however, none of the same defects in complex I assembly are seen in mitochondria isolated from brain tissue
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respiratory system
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• at 12 weeks of age, both absolute lung weight and lung weight normalized to femur length is significantly higher than in wild-type controls, suggesting lung congestion from left ventricular hypertrophy
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liver/biliary system
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• at 12 weeks of age, both absolute liver weight and liver weight normalized to femur length is significantly lower than in wild-type controls
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immune system
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• after stimulation with LPS, bone marrowderived macrophages (BMDMs) derived from 12-week-old mice show a normal TLR response with no major changes in the protein levels and phosphorylation of p38-MAPK and JNK relative to wild-type BMDMs
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• FACS analysis of whole blood from 12-week-old mice shows a small reduction in the % of circulating leukocytes but no changes in the % of monocytes or neutrophils
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• FACS analysis of whole-blood from 12-week-old mice shows a small reduction in the % of circulating macrophages
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hematopoietic system
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• FACS analysis of whole blood from 12-week-old mice shows a small reduction in the % of circulating leukocytes but no changes in the % of monocytes or neutrophils
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• FACS analysis of whole-blood from 12-week-old mice shows a small reduction in the % of circulating macrophages
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growth/size/body
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• at 12 weeks of age, both absolute heart weight and heart weight normalized to femur length is significantly higher than in wild-type controls
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• at 12 weeks of age, both absolute lung weight and lung weight normalized to femur length is significantly higher than in wild-type controls, suggesting lung congestion from left ventricular hypertrophy
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