Submitted on February 15, 2006
Accepted on October 23, 2006
Respiratory impairment in a mouse model of Amyotrophic Lateral Sclerosis
Clarke G Tankersley1*, Christine Haenggeli2, and Jeffrey D. Rothstein3
1 Environmental Health Sciences, Johns Hopkins Medical Institutes, Baltimore, Maryland, United States
2 Neurology, Johns Hopkins Medical Institutes, Baltimore, Maryland, United States
3 Neurology, Johns Hopkins Medical Institutes, Baltimore, Maryland, United States; Neuroscience, Johns Hopkins Medical Institutes, Baltimore, Maryland, United States
* To whom correspondence should be addressed. E-mail: ctankers{at}jhsph.edu.
Amyothrophic lateral sclerosis (ALS) is a lethal neuromuscular disease associated with the degeneration of spinal motor neurons, and atrophy of respiratory muscles. Overexpression of superoxide dismutase-1 (SOD1) gene mutations in mice recapitulates several of the disease characteristics of ALS. The current study is intended to evaluate an age-dependent progression of respiratory complications in SOD1G93A mutant mice. Baseline measurements of breathing pattern (i.e. breathing frequency (f) and tidal volume (VT)), minute ventilation (VE), and metabolism (i.e. oxygen consumption (VO2) and carbon dioxide production (VCO2)) were repeatedly sampled at variable time-points between 10 and 20 wks of age using whole-body plethysmography. VE was also measured during 5-min challenges of hypercapnia (5%CO2) and hypoxia (10%O2). At baseline, breathing characteristics and metabolism remained relatively unchanged from 10 to 14 wks of age. From 14 to 18 wks of age, there were significant (P<0.05) increases in baseline VT, VE and the ventilatory equivalent for O2(VE/VO2). After 18 wks of age, there was a rapid decline in VE due to significant (P < 0.05) reductions in both f and VT. Hypercapnic VE responses were also significantly (P<0.05) elevated at 18wks due to an augmented VT response, and declined rapidly after 18wks of age. The phenotypic profile of SOD1 mutant mice was apparently unique since similar changes in respiration and metabolism were not observed in SOD1 controls. The current results outline the magnitude and time course of respiratory complications in SOD1G93A mutant mice as the progression of disease occurs in this mouse model of ALS.
