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Phrenic, but not hypoglossal, motor output is diminished in a rat model of amyotrophic lateral sclerosis (ALS)
Author(s) -
Nashold Lisa J,
Wilkerson J E R,
Satriotomo I,
Dale E A,
Svendsen C N,
Mitchell G S
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1212-b
Subject(s) - amyotrophic lateral sclerosis , hypercapnia , respiratory system , medicine , ventilation (architecture) , anesthesia , hypoglossal nerve , phrenic nerve , pathology , disease , mechanical engineering , tongue , engineering
ALS causes motoneuron degeneration and, ultimately, patient death by respiratory failure. We investigated the capacity to maintain respiratory motor output in a transgenic rat model of ALS that over expresses a mutated form of superoxide dismutase‐1 (SOD1 G93A ). Phrenic and hypoglossal nerve output were recorded from anesthetized, vagotomized and ventilated end‐stage SOD1 G93A or wild type rats at different levels of respiratory drive regulated by controlling arterial PCO 2 levels between the apneic CO 2 ‐threshold (SOD1 G93A : 41±1 mmHg; wild type: 42±2 mmHg) and severe hypercapnia (90 mmHg). During baseline conditions (3 mmHg above CO 2 ‐threshold), phrenic burst amplitude was significantly less in SOD1 G93A (1.2±0.2 Volts) vs wild type rats (2.8±0.4 V; p < 0.01), a relationship that persisted during hypercapnia (SOD1 G93A : 2.4±0.5 V; wild type: 4.6±0.4 V; p < 0.01). Immunohistochemistry showed decreased motoneuron cell counts in the phrenic motor nucleus. In contrast, XII activity was similar in SOD1 G93A and wild type rats in all conditions studied, and XII motoneuron cell counts were normal relative to wild type rats. As ventilation is normal or enhanced during hypercapnia in unanesthetized SOD1 G93A rats, compensatory mechanisms preserve the capacity to breathe until late stage disease. Whereas ventilation in intact rats may not be a reliable quantitative index of respiratory compromise in this animal model, phrenic nerve recordings demonstrate clear functional impairment and may be a useful indicator of disease progression. Supported by ALS Association and NIH HL 89209, HL 65383 and HL07654.