Phenotypes Associated with This Genotype

Genotype
MGI:8275124

• Allelic Composition: Orai1^em1Dirr/Orai1⁺
• Genetic Background: C57BL/6J-Orai1^em1Dirr

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

muscle

muscle phenotype ( J:376832 )

N • 8-month-old extensor digitorum longus (EDL) muscle shows absence of significant dystrophic features, muscle regeneration, and central nuclei and EDL and soleus (SOL) muscles show normal fiber size and fiber type distribution

abnormal muscle fiber mitochondrial morphology ( J:376832 )

• EDL muscles from 8-month-old mice show an increase in the number of severely altered mitochondria (disrupted external membranes, vacuolation of internal membranes, and/or myelin figure formation), morphologically normal mitochondria that are larger in size (mitochondrial swelling), and reduced number of mitochondria at the A band

decreased skeletal muscle fiber mitochondrial DNA content ( J:376832 )

• modest, but significant, reduction in mitochondrial content in skeletal muscle of 8-month-old mice

abnormal hypaxial muscle morphology ( J:376832 )

• EDL muscle shows tubular aggregates at 12 and 18 months of age

• fast-twitch extensor digitorum longus (EDL) and flexor digitorum brevis (FDB) muscles of 8-month-old mice show honeycomb-like tubular aggregates

• tubular aggregates are seen in about 30% of EDL fibers, about 10% of FDB fibers, and about 20% of tibialis anterior fibers at 8 months of age

• muscles from 8-month-old mice exhibit increases in both the average number of tubular aggregates/fiber and tubular aggregate size

• however, no tubular aggregates are seen in EDL at 4 months of age

abnormal muscle physiology ( J:376832 )

• myotubes, embryonic myofibers, and FDB fibers isolated from 2-5-week-old mice exhibit elevated constitutive Ca2+ entry (in the absence of prior Ca2+ store depletion) which is abolished after 4 months of age

• myotubes/fibers show reduced store-operated Ca2+ entry (SOCE) following sarcoplasmic reticulum (SR) Ca2+ store depletion across all ages

• total releasable Ca2+ store content in muscle is increased in 2-week-old and 8-month-old mice

impaired muscle contractility ( J:376832 )

• EDL and SOL muscles from 8-month-old mice show a reduction in specific force production under high stimulation frequencies

• EDL muscles exhibit a decrease in the maximum rate of force generation during tetanic stimulation

• EDL muscles stimulated with 60 trains of repetitive 50 Hz stimulation show a decrease in specific force for several stimulus trains after the second stimulus

impaired muscle relaxation ( J:376832 )

• EDL and SOL muscles from 8-month-old mice show a modest reduction in the maximum rate of force relaxation (-dF/dt) during tetanic stimulation (150 Hz)

increased muscle fatigability ( J:376832 )

• EDL muscles stimulated with 60 trains of repetitive 50 Hz stimulation show a decrease in specific force for several stimulus trains after the second stimulus

• however, in SOL muscles stimulated with 60 trains of repetitive 50 Hz stimulation, peak specific force during the second half of the repetitive stimulation is increased suggesting that SOL muscles are more resistant to exercise-induced fatigue

• the overall rate of force decline after about 20 repetitive stimuli is somewhat reduced in both EDL and SOL muscles

• both EDL and SOL muscles exhibit reduced peak specific forces, prolonged time for 50% force decay, and decreased maximum rate of force decay during a prolonged tetanic (150 Hz) stimulation

muscle weakness ( J:376832 )

• mice exhibit muscle weakness by 8 months of age

behavior/neurological

decreased grip strength ( J:376832 )

• grip strength normalized to body mass is reduced in 8-month-old mice

pup cannibalization ( J:376832 )

♀ • females mated with wild-type males commit parental infanticide after delivery

♀ • however, males mated with wild-type females are able to produce offspring

impaired exercise endurance ( J:376832 )

• 8-month-old mice rest 23% more during a 1-hour treadmill endurance task and fall 3x more frequently during the 1-hour rotarod endurance task

cellular

abnormal muscle fiber mitochondrial morphology ( J:376832 )

• EDL muscles from 8-month-old mice show an increase in the number of severely altered mitochondria (disrupted external membranes, vacuolation of internal membranes, and/or myelin figure formation), morphologically normal mitochondria that are larger in size (mitochondrial swelling), and reduced number of mitochondria at the A band

decreased skeletal muscle fiber mitochondrial DNA content ( J:376832 )

• modest, but significant, reduction in mitochondrial content in skeletal muscle of 8-month-old mice

abnormal mitochondrial physiology ( J:376832 )

• basal and FCCP-sensitive TMRE (a fluorescent indicator of mitochondrial membrane potential) responses are increased in FDB fibers, indicating a more negative mitochondrial membrane potential

• activity of Complex I, III, and V are increased in mitochondria from hindlimb skeletal muscle of 8-month-old mice

• maximal ADP-stimulated oxygen consumption rate (State III) is reduced in mitochondria of hindlimb skeletal muscle, while oxygen consumption rates of all other respiratory states (States II, IV, and V) are not different

• the respiratory control ratio is reduced in mitochondria from skeletal muscle

oxidative stress ( J:376832 )

• rate of mitochondrial ROS production in FDB fibers is increased, indicating increased mitochondrial oxidative stress

growth/size/body

decreased total tissue mass ( J:376832 )

• modest, but significant reduction in body mass at 8 and 12 months of age

• however, extensor digitorum longus muscle mass is not different at 4, 8, or 12 months and soleus muscle mass is not different at 8 months

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:376832 )

N • blood platelet counts, mean platelet volume, red blood cell number, hemoglobin, hematocrit, and white blood cells are not significantly altered at 8 months of age and mice show normal hemostasis with no change in blood clotting rate

impaired exercise endurance ( J:376832 )

• 8-month-old mice rest 23% more during a 1-hour treadmill endurance task and fall 3x more frequently during the 1-hour rotarod endurance task

decreased circulating calcium level ( J:376832 )

• 27% reduction in whole blood ionized calcium at 8 months of age

• however, all other blood parameters, including sodium, potassium, glucose, and pH are unaltered

increased circulating creatine kinase level ( J:376832 )

• serum creatine kinase levels in 8 month old mice are increased about 3-fold, consistent with a low level of muscle damage

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
tubular aggregate myopathy 2		DOID:0080686	OMIM:615883	J:376832