Phenotypes associated with this allele

• Allele Symbol: Cacna1s^tm1.1Arte
• Allele Name: targeted mutation 1.1, TaconicArtemis
• Allele ID: MGI:5819113
• Summary: 1 genotype

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Cacna1s^tm1.1Arte/Cacna1s^tm1.1Arte	involves: C57BL/6N	MGI:5824112

Genotype
MGI:5824112

hm1

• Allelic Composition: Cacna1s^tm1.1Arte/Cacna1s^tm1.1Arte
• Genetic Background: involves: C57BL/6N

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

behavior/neurological

decreased grip strength ( J:235534 )

• at 6 months of age, grip force of the front paws is significantly reduced in a wire hang test

• however, overall muscle strength (wire hang test), home cage activity, and motor performance (rotarod test) remain relatively normal at 2 and 8 months of age

decreased aerobic running capacity ( J:235534 )

• analysis of voluntary wheel running activity over 7-day period showed that both distance run and time spent running per day are significantly reduced relative to wild-type controls

muscle

muscle phenotype ( J:235534 )

N • at 6 months of age, soleus and extensor digitorum longus (EDL) muscles exhibit normal myofiber histology with no apparent increase in centrally located nuclei relative to wild-type controls

N • no severe myotonic dystrophy symptoms are observed

abnormal skeletal muscle fiber mitochondrial morphology ( J:235534 )

• at 4-5 months of age, soleus and EDL muscles display distorted and lysed mitochondria along with a 4.5-fold increase in the fraction of damaged mitochondria

• however, myofibrils and EC coupling membranes appear normal

abnormal skeletal muscle fiber type ratio ( J:235534 )

• both soleus and EDL muscles exhibit a shift in fiber type composition towards slower fiber types

• soleus muscles show a 48% increase in the fraction of type I fibers, mainly at the expense of type IIA and mixed fibers

• EDL muscles show a 26% reduction in the fraction of type IIB fibers, whereas the fractions of IIA, IIX and mixed fibers are increased 2- to 3-fold; no type I fibers are observed

abnormal muscle physiology ( J:235534 )

• both soleus and EDL muscles exhibit significantly reduced fatigue relative to wild-type controls

• relative reduction of muscle force at the 100th and 150th tetanus is significantly lower than that in wild-type muscles, indicating increased fatigue resistance

impaired skeletal muscle contractility ( J:235534 )

• isolated soleus and EDL muscles exhibit a significant reduction in contractile force in response to a single electrical stimulus (twitch) and in response to high-frequency trains of stimuli (tetanus)

• both muscles reach the half-maximal value and the plateau of contractile force at lower frequencies than control muscles, as reflected by a left shift of the force frequency curve and a reduction of the frequency of the half-maximal tetanic force

abnormal muscle electrophysiology ( J:235534 )

• isolated flexor digitorum brevis (FDB) muscle fibers exhibit increased calcium influx during excitation-contraction (EC) coupling, altered calcium handling during refilling of sarcoplasmic reticulum (SR) calcium stores, and spontaneous focal calcium transients (calcium sparklets), unlike wild-type muscle fibers

• calcium sparklets occur only in high extracellular calcium concentrations and are blocked by addition of nisoldipine (an L-type calcium channel blocker)

homeostasis/metabolism

decreased aerobic running capacity ( J:235534 )

• analysis of voluntary wheel running activity over 7-day period showed that both distance run and time spent running per day are significantly reduced relative to wild-type controls

abnormal calcium ion homeostasis ( J:235534 )

• adult mice exhibit increased calcium influx during EC coupling, altered calcium homeostasis, and spontaneous calcium sparklets in isolated muscle fibers

abnormal enzyme/coenzyme activity ( J:235534 )

• at 7 weeks of age, succinate dehydrogenase (SDH) activity is markedly increased in soleus and EDL muscles; specifically, soleus shows a loss of fibers with lower SDH activity, whereas EDL shows an increase in high SDH activity fibers

• surprisingly, at 6 and 12 months of age, SDH activity is significantly reduced in both soleus and EDL muscles, indicating that the initial increase of oxidative metabolism noted in young mice is reversed at >6 months of age; this is more pronounced in soleus than in EDL but equally affects fibers with low and high SDH activity

cellular

abnormal skeletal muscle fiber mitochondrial morphology ( J:235534 )

• at 4-5 months of age, soleus and EDL muscles display distorted and lysed mitochondria along with a 4.5-fold increase in the fraction of damaged mitochondria

• however, myofibrils and EC coupling membranes appear normal

decreased mitochondrial number ( J:235534 )

• at 4-5 months of age, the mitochondrial content (% area occupied by intact mitochondria) in soleus and EDL muscles is reduced to ~50% of that in wild-type controls

decreased mitochondrial size ( J:235534 )

• at 4-5 months of age, soleus and EDL muscles display a reduction in the average size of healthy mitochondria

dilated mitochondrion ( J:235534 )

• at 4-5 months of age, soleus and EDL muscles show dilated mitochondria

abnormal mitochondrial physiology ( J:235534 )

• mature soleus and EDL muscles exhibit mitochondrial damage caused by calcium overload due to increased activity-dependent and spontaneous calcium influx and altered calcium homeostasis