Age-dependent poliomyelitis in mice is associated with respiratory failure and viral replication in the central nervous system and lung.
Age-dependent poliomyelitis (ADPM) is a virally induced neuroparalytic disease of mice and a model for amyotrophic lateral sclerosis (ALS). ADPM is triggered in genetically susceptible mice by immunosuppression and infection with lactate dehydrogenase-elevating virus (LDV). Both ADPM and ALS are characterized by progressive degeneration of anterior horn motor neurons, and death in ALS is usually associated with respiratory failure. To assess respiratory function in ADPM, we investigated ventilation in conscious control and LDV-infected C58/J mice breathing air and then 6.5% CO(2) in O(2). Three days after LDV infection, ventilation in response to CO(2) was half of that compared to the uninfected state, but become normalized by 10 days. Administration of cyclophosphamide alone (200 mg/kg, ip), an immunosuppressant, had no effect on ventilation. Induction of ADPM by concomitant administration of LDV to cyclophosphamide-treated mice resulted in altered gait, hindlimb paralysis, wasting, decreased metabolism, and decreased body temperature by 4 degrees C relative to controls. Compared to baseline values, mice with ADPM had decreased tidal volume and ventilation while breathing air, and while exposed to the CO(2) challenge they were unable to increase tidal volume, frequency of breathing, or ventilation. Using in situ hybridization, LDV replication was noted within the spinal cord, brain, and lung, but not in the diaphragm. Thus, respiratory failure is a contributory mechanism leading to death in ADPM and is associated with LDV replication in the CNS and lung. This animal model may be useful to investigate physiological and molecular mechanisms associated with the development of respiratory failure in neurodegenerative diseases.
Schlenker
E H
EH
Division of Basic Biomedical Sciences, University of South Dakota School of Medicine, Vermillion, South Dakota 57069, USA.
Jones
Q A
QA
Rowland
R R
RR
Steffen-Bien
M
M
Cafruny
W A
WA
D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology; D000818:Animals; D018174:Arterivirus Infections / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D001831:Body Temperature; D001835:Body Weight; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005260:Female; D007772:Lactate dehydrogenase-elevating virus / Q000254:growth & development*; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D051379:Mice; D008815:Mice, Inbred Strains; D011051:Poliomyelitis / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D012119:Respiration; D012131:Respiratory Insufficiency / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D014779:Virus Replication