Analysis Tools
mortality/aging
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• average lifespan is 102 +/- 5 days for females and 107 +/- 4 days for males as determined by their humane endpoint (time taken to lose 20% of peak body weight or an inability to right themselves within 20 s when placed on their sides)
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growth/size/body
weight loss
(
J:229162
)
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• body weight is significantly reduced from 3 weeks in females and from 4 weeks in males and continues to significantly decrease to 15-16 weeks of age
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behavior/neurological
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• abnormal pulling in of all four limbs when held by the tail at 15-weeks of age
• ~55% display limb grasping of front or rear legs at 6 weeks of age
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• significant decrease in the latency to fall in an accelerated Rotarod test at 6 and 13 weeks of age
• all mice are severely impaired when hanging from a wire by their forelimbs at 6 weeks of age
• age-dependent deterioration in motor coordination as shown by significantly increased number of rear leg errors at 14 weeks versus 7 weeks of age
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• abnormal placement of the limbs, esp. hindlimbs, when walking across a wire grate
• significantly more front and rear leg placement errors than in controls in the Locotronic system at 7 and 14 weeks of age
• significant increase in rear leg errors in the Locotronic system at 14 weeks versus 7 weeks of age
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• severe reduction in grip strength at 6 and 13 weeks of age
• all mice are unable to maintain grip when made to walk down a vertical wire grate at 6 weeks of age
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• both sexes develop an abnormal gait from 3 weeks of age that worsens with age
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• progressive reduction in distance moved and velocity in the open field test at 14 weeks versus 7 weeks of age
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• all mice display negative geotaxis deficits at 6 weeks of age
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skeleton
muscle
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• significant atrophy (80%), reduced fiber size, centralized nuclei, increased proportion of slower twitch, type I/highly oxidative muscle fibers, and extensive areas of fibrosis in the gastrocnemius at 14 weeks of age
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• reduced gastrocnemius weight at 14 weeks but not at 6 weeks of age
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• increased proportion of slower twitch, type I/highly oxidative muscle fibers in the soleus at 14 weeks of age
• significantly fewer muscle fibers with increased spread of fiber size, ranging from very small to very large muscle fibers, in the soleus at 14 weeks relative to wild-type controls
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• reduced soleus weight at 14 weeks but not at 6 weeks of age
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• reduced tibialis anterior weight at 14 weeks but not at 6 weeks of age
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• increased spread of fiber size, ranging from very small to very large muscle fibers, in the soleus at 14 weeks of age
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• centralized nuclei in the gastrocnemius at 14 weeks of age
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• significantly fewer muscle fibers in the soleus at 14 weeks of age
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• increased proportion of slower twitch, type I/highly oxidative muscle fibers in the gastrocnemius and soleus at 14 weeks of age relative to wild-type controls
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• progressive, severe muscle atrophy
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• extensive muscle fiber atrophy in the gastrocnemius at 14 weeks of age
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• extensive areas of the gastrocnemius are fibrotic at 14 weeks of age
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• when repeatedly stimulated in a muscle fatigue assay, fast twitch EDL muscles become significantly more fatigue resistant as mice age, a feature usually observed in slow twitch muscles
• by 15 weeks of age, the fatigue index (FI) of EDL muscles is increased by 66.7% relative to wild-type controls (0.69 +/- 0.05 versus 0.23 +/- 0.02; an FI of 1.0 indicates complete fatigue resistance)
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• maximum isometric force (tetanic tension) generated from the tibialis anterior (TA) is reduced by ~65% at 7 weeks and by ~75% at 15 weeks of age
• tetanic tension of extensor digitorum longus (EDL) muscles is reduced by ~20% at 7 weeks and by ~50% at 15 weeks of age
• TA muscles are affected earlier and more severely than EDL muscles
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nervous system
| N |
• grossly normal brain anatomy with no evidence of reactive gliosis at 15 weeks of age
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• widespread reactive gliosis, along with >50% motor neuron loss, in lumbar spinal cord sections at 15 weeks of age, unlike in wild-type or heterozygous controls
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astrocytosis
(
J:229162
)
|
• severe astrocytosis in lumbar spinal cord sections at 15 weeks of age
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microgliosis
(
J:229162
)
|
• severe microgliosis in lumbar spinal cord sections at 15 weeks of age
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• active cell death in the ventral spinal cord, as shown by TUNEL staining of the lumbar L3-L4 region at 15 weeks of age
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• significant reduction in axonal diameter on the sciatic nerve at P9 relative to wild-type controls
• shift in the frequency distribution towards a thinner axon diameter and an increased g-ratio in lumbar L4 and L5 dorsal roots at P9
• however, axon morphology from ventral roots is normal and no neuronal loss is noted at P9
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• signs of chromatolysis in some L4 and L5 dorsal root ganglia at 15 weeks of age
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• numerous DRG neurons appear shrunken and irregular and some show signs of chromatolysis, with flattened nuclei at 15 weeks of age
• however, DRG morphology is normal at P9
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• at 15 weeks of age
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• at 15 weeks of age
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• numerous L4 and L5 dorsal root ganglia are smaller than wild-type at 15 weeks of age
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• progressive deficits in both the motor and sensory neuronal systems of the spinal cord
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• progressive neurodegeneration in both motor and sensory neurons of the spinal cord
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• number of surviving functional motor units innervating the EDL muscle is significantly reduced relative to wild-type controls at 7 weeks (26 +/- 0.9 versus 31 +/- 0.4 motor units) and further reduced by 15 weeks of age (23 +/- 1 versus 31 +/- 0.5 motor units)
• widespread loss of fibers, active degeneration of motor axons with no signs of regeneration and normal myelination in the lumbar L4 and L5 ventral roots at 15 weeks of age
• in the lumbar spinal cord (L3-L6), motor neuron number is reduced by 35% at 7 weeks and by a further 15% at 15 weeks of age, totaling a motor neuron loss of 50% at 15 weeks of age
• occasional vacuolated motor neurons seen at 15 weeks of age, likely undergoing cell death
• however, motor neuron survival in the sciatic pool is normal at P9
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• active degeneration of motor axons in the lumbar L4 and L5 ventral roots at 15 weeks of age
• loss of both large and small sensory axons in the L4 and L5 dorsal roots at 15 weeks of age; degeneration of myelinated and unmyelinated axons with no evidence of axonal regeneration or demyelination
• degeneration of ascending sensory axons with no apparent defects in the descending spinal cord tracts
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cellular
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• widespread reactive gliosis, along with >50% motor neuron loss, in lumbar spinal cord sections at 15 weeks of age, unlike in wild-type or heterozygous controls
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astrocytosis
(
J:229162
)
|
• severe astrocytosis in lumbar spinal cord sections at 15 weeks of age
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microgliosis
(
J:229162
)
|
• severe microgliosis in lumbar spinal cord sections at 15 weeks of age
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• active cell death in the ventral spinal cord, as shown by TUNEL staining of the lumbar L3-L4 region at 15 weeks of age
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• increased basal mitochondrial membrane potential in embryonic motor neurons derived from mutant mice, as shown by a 27% increase in tetramethylrhodamine methylester (TMRM) signal relative to wild-type motor neurons
• significant reduction of mitochondrial membrane potential in embryonic motor neurons (~17% fall in TMRM signal) following exposure to oligomycin (an inhibitor of the F1FO-ATP synthase), unlike in wild-type motor neurons
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• functional inhibition of the NADH-dependent (Complex I) within the mitochondrial electron transport chain and activation of Complex II in embryonic motor neurons derived from mutant mice
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• NADH redox index is increased in mutant embryonic motor neurons (58% +/- 4%) relative to wild-type motor neurons (39% +/- 3%)
• FADH redox index is increased in mutant embryonic motor neurons (89% +/- 6%) relative to wild-type motor neurons (49% +/- 3%)
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hematopoietic system
microgliosis
(
J:229162
)
|
• severe microgliosis in lumbar spinal cord sections at 15 weeks of age
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immune system
microgliosis
(
J:229162
)
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• severe microgliosis in lumbar spinal cord sections at 15 weeks of age
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limbs/digits/tail
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• significant atrophy (80%), reduced fiber size, centralized nuclei, increased proportion of slower twitch, type I/highly oxidative muscle fibers, and extensive areas of fibrosis in the gastrocnemius at 14 weeks of age
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• reduced gastrocnemius weight at 14 weeks but not at 6 weeks of age
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• increased proportion of slower twitch, type I/highly oxidative muscle fibers in the soleus at 14 weeks of age
• significantly fewer muscle fibers with increased spread of fiber size, ranging from very small to very large muscle fibers, in the soleus at 14 weeks relative to wild-type controls
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• reduced soleus weight at 14 weeks but not at 6 weeks of age
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• reduced tibialis anterior weight at 14 weeks but not at 6 weeks of age
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