Analysis Tools
mortality/aging
| N |
• homozygotes exhibit no obvious progeroid phenotype
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• homozygotes invariably die between P16 and P18, likely due to combined muscle weakness and metabolic complications
• treatment with the alpha- and beta-adrenergic receptor antagonist labetalol from P10 onward leads to earlier postnatal death relative to wild-type and heterozygous controls
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growth/size/body
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• autopsy at P17 revealed increased intestinal gas
• however, no obvious alterations in food content or GI tract morphology are observed
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• homozygotes first exhibit decreased body weight at P7
• body weight peaks at P13 and decreases slightly thereafter, reaching ~50% of wild-type body weight at P16
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• onset of postnatal growth retardation is first noted at P7
• overall body growth ceases between P13 and P18
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behavior/neurological
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• foraging, assessed by the ability to suckle, is reduced only at days P16-P18
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• homozygotes are born phenotypically normal but appear scruffy at P16
• grooming behavior is normal until P16
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• at P15, homozygotes show reduced muscular strength: lag time dropping from grid is 0.9 +/- 0.5 sec relative to 6.7 +/- 1.4 sec in wild-type controls
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• homozygotes appear hunch-backed at P16
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• abnormal gait, characterized by splayed hind legs from day P13 onwards
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cardiovascular system
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• at P15, left ventricle (LV) cardiac myocytes are smaller than wild-type
• however, no cardiac myocyte degeneration, fibrosis or obvious defects in interstitial spaces and Z-disc organization are observed
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• mutant LV myocytes fail to undergo postnatal hypertrophy upon cell cycle exit in the first week after birth
• at P11, normal postnatal cardiac hypertrophy is significantly impaired, with a ~2-fold reduction in cross-sectional area counts
• however, no differences in cardiac proliferative activity (PCNA, Ki67) are observed in the LV
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• LV weight, normalized to tibia length, is reduced by 14% at P11 and up to 47% at P15 relative to age-matched wild-type controls
• echocardiography confirmed impaired postnatal cardiac hypertrophy, as shown by lower relative LV weight at P17
• however, fractional shortening (FS), an indicator for LV contractility, is normal at P10, P13 and P17
• no signs of LV dilatation nor thinning of the LV wall are observed
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• ECG analysis revealed a significantly lower heart rate at P17
• 3 days after the start (P10) of labetalol treatment, homozygotes show a significantly decreased heart rate (396 +/- 51 bpm to 232 +/- 20 bpm), unlike similarly-treated wild-type and heterozygous controls
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• the RR interval is significantly increased at P17 but not earlier (P10, P13)
• however, no differences in P wave duration, PR interval, QRS time, or QT time are observed
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• 3 days after the start (P10) of labetalol treatment, homozygotes show a significantly increased P time (from 23.7 +/- 2.6 ms to 29.8 +/- 3.2 ms), unlike similarly-treated wild-type and heterozygous controls
• however, untreated homozygotes show no significant differences in P wave duration relative to wild-type controls
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homeostasis/metabolism
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• at P12, C12-carnitine levels are significantly reduced relative to wild-type and heterozygous controls
• at P16, acylcarnitine analysis revealed reduced free carnitine in combination with elevated acetylcarnitine and long chain acylcarnitines, consistent with increased fatty acid catabolism
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hypoglycemia
(
J:221850
)
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• at P16, homozygotes are hypoglycemic while blood lactate levels remain normal
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• at P16, betahydroxybutyrate levels are significantly increased relative to wild-type controls, indicating increased ketogenesis
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• at P12, blood lactate levels are significantly reduced
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• blood creatine kinase levels are significantly elevated at P15, but not at P9, relative to wild-type controls
• however, blood urea and creatinine levels are not significantly altered at P15
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• core body temperature is significantly lower both at P9 and at P15 relative to wild-type controls
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• at P18, homozygotes exhibit no detectable glycogen deposits in the liver, unlike wild-type and heterozygous controls
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muscle
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• at P15, left ventricle (LV) cardiac myocytes are smaller than wild-type
• however, no cardiac myocyte degeneration, fibrosis or obvious defects in interstitial spaces and Z-disc organization are observed
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• quadriceps muscle weight, normalized to tibia length, is significantly reduced at P15, but not at P9, relative to wild-type controls
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• at P15, homozygotes display smaller quadriceps skeletal myocytes than wild-type controls
• however, no signs of immature muscle fibers or centrally located nuclei, fibrosis or disorganized Z-discs are observed
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• although normal at P9, quadriceps myocyte cross-sectional area is significantly decreased at P15 relative to wild-type controls
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adipose tissue
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• at P15, homozygotes display reduced subcutaneous adipose tissue relative to wild-type controls
• subcutaneous adipose tissue weight, normalized to tibia length, is normal at P5, but significantly reduced at P14 relative to wild-type controls
• however, gonadal fat patches and subscapular brown adipose tissue show no obvious mass reduction
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• ex vivo, MEFs isolated from E12.0 mutant embryos show significantly impaired adipogenic differentiation, as revealed by Red O lipid staining at 16 days post-induction
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liver/biliary system
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• at P18, homozygotes exhibit no detectable glycogen deposits in the liver, unlike wild-type and heterozygous controls
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integument
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• at P15, homozygotes display reduced subcutaneous adipose tissue relative to wild-type controls
• subcutaneous adipose tissue weight, normalized to tibia length, is normal at P5, but significantly reduced at P14 relative to wild-type controls
• however, gonadal fat patches and subscapular brown adipose tissue show no obvious mass reduction
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cellular
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• ex vivo, MEFs isolated from E12.0 mutant embryos show significantly impaired adipogenic differentiation, as revealed by Red O lipid staining at 16 days post-induction
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• analysis of mitochondrial complex activities in LV cardiac muscle at P15 revealed a slight but significant decrease in complex II activity relative to wild-type controls
• however, no changes in mitochondrial DNA copy numbers are noted in heart or quadriceps skeletal muscle at P15
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digestive/alimentary system
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• autopsy at P17 revealed increased intestinal gas
• however, no obvious alterations in food content or GI tract morphology are observed
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craniofacial
| N |
• homozygotes exhibit no obvious dentition defects
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skeleton
| N |
• homozygotes exhibit no obvious bone abnormalities
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limbs/digits/tail
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• quadriceps muscle weight, normalized to tibia length, is significantly reduced at P15, but not at P9, relative to wild-type controls
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