Respiratory impairment in a mouse model of amyotrophic lateral sclerosis

Tankersley, Clarke G.; Haenggeli, Christine; Rothstein, Jeffery D.

doi:10.1152/japplphysiol.00193.2006

Cited by 57 publications

(49 citation statements)

References 38 publications

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“…In this study, respiratory function and diaphragm muscle tension was investigated after female B6SJL-SOD1 G93A mice reached a 40% deficit in forelimb grip strength, or approximately 18 weeks of age. Consistent with prior work [20] respiratory function did not appear to be compromised in B6SJL-SOD1 G93A mice at this stage in their disease progression since breath frequency and tidal volume were not significantly different from age-matched WT mice at room air or when exposed to a 5% hypercapnic challenge (data not shown). Treatment with tirasemtiv did lead to decreased breath frequency and a significant increase in tidal volume (Figure 7A) which are indicative of an effect on diaphragm function.…”

Section: Discussionsupporting

confidence: 89%

Fast Skeletal Muscle Troponin Activator tirasemtiv Increases Muscle Function and Performance in the B6SJL-SOD1G93A ALS Mouse Model

et al. 2014

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Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease characterized by progressive motor neuron loss resulting in muscle atrophy, declining muscle function, and eventual paralysis. Patients typically die from respiratory failure 3 to 5 years from the onset of symptoms. Tirasemtiv is a fast skeletal troponin activator that sensitizes the sarcomere to calcium; this mechanism of action amplifies the response of muscle to neuromuscular input producing greater force when nerve input is reduced. Here, we demonstrate that a single dose of tirasemtiv significantly increases submaximal isometric force, forelimb grip strength, grid hang time, and rotarod performance in a female transgenic mouse model (B6SJL-SOD1G93A) of ALS with functional deficits. Additionally, diaphragm force and tidal volume are significantly higher in tirasemtiv-treated female B6SJL-SOD1G93A mice. These results support the potential of fast skeletal troponin activators to improve muscle function in neuromuscular diseases.

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Section: Discussionsupporting

confidence: 89%

Fast Skeletal Muscle Troponin Activator tirasemtiv Increases Muscle Function and Performance in the B6SJL-SOD1G93A ALS Mouse Model

et al. 2014

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“…Growth rates for SOD1-G93A and control mice were similar until a decline began in the affected mice at approximately 95 days of age. Other studies reported differences in body weight between SOD1-G93A and control mice emerging much later, from approximately 98 days to approximately 126 days (Weydt et al, 2003;Tankersley et al, 2007). Here, we observed a consistent significant difference in weight beginning at 108 days of age.…”

Section: Body Weightsupporting

confidence: 87%

Time-course and characterization of orolingual motor deficits in B6SJL-Tg(SOD1-G93A)1Gur/J mice

2008

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Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease affecting upper and lower motor neurons. Symptom onset may occur in the muscles of the limbs (spinal onset) or those of the head and neck (bulbar onset). Bulbar involvement is particularly important in ALS as it is associated with increased morbidity and mortality. The purpose of this study was to characterize bulbar motor deficits in the SOD1-G93A mouse model of familial ALS. We measured orolingual motor function by placing thirsty mice in a customized operant chamber that allows for measurement of tongue force and lick rhythm as animals lick water from an isometric disc. Testing spanned the pre-symptomatic, symptomatic, and end-stage segments of the disease. Rotarod performance, fore-and hindlimb grip strength, and locomotor activity were also monitored regularly during this period. We found that spinal involvement was apparent first, with both fore-and hindlimb grip strength being affected in SOD1-G93A mice from the onset of testing (64 days of age). Rotarod performance was affected by 71 days of age. Locomotor activity was not affected, even near end-stage. Bulbar involvement appeared much later, with tongue motility being affected by 100 days of age. Tongue force was affected by 115 days of age. To our knowledge, these findings are the first to describe the onset of bulbar v. spinal motor signs and characterize orolingual motor deficits in this preclinical model of ALS.

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“…As H 2 CO 3 dissociates (and CO 2 is expelled by the lungs) H + removal (alkalization) is promoted as H + combines with HCO 3 − . Given these processes, it is not surprising that an increase in breathing frequency, tidal volume, and CO 2 production was found to occur in SOD1 G93A mice several weeks before death (29). Sustained hyperventilation leading to CO 2 depletion within the CNS, however, will initiate vasoconstriction, reduced blood flow, ischemia, and edema (30)-all occurring in the spinal cord of SOD1 G93A mice before motor neuron degeneration (31,32).…”

Section: Discussionmentioning

confidence: 99%

Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis

Dodge¹,

Treleaven²,

Fidler³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

110

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Metabolic dysfunction is an important modulator of disease course in amyotrophic lateral sclerosis (ALS). We report here that a familial mouse model (transgenic mice over-expressing the G93A mutation of the Cu/Zn superoxide dismutase 1 gene) of ALS enters a progressive state of acidosis that is associated with several metabolic (hormonal) alternations that favor lipolysis. Extensive investigation of the major determinants of H + concentration (i.e., the strong ion difference and the strong ion gap) suggests that acidosis is also due in part to the presence of an unknown anion. Consistent with a compensatory response to avert pathological acidosis, ALS mice harbor increased accumulation of glycogen in CNS and visceral tissues. The altered glycogen is associated with fluctuations in lysosomal and neutral α-glucosidase activities. Disease-related changes in glycogen, glucose, and α-glucosidase activity are also found in spinal cord tissue samples of autopsied patients with ALS. Collectively, these data provide insights into the pathogenesis of ALS as well as potential targets for drug development.

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Respiratory impairment in a mouse model of amyotrophic lateral sclerosis

Cited by 57 publications

References 38 publications

Fast Skeletal Muscle Troponin Activator tirasemtiv Increases Muscle Function and Performance in the B6SJL-SOD1G93A ALS Mouse Model

Fast Skeletal Muscle Troponin Activator tirasemtiv Increases Muscle Function and Performance in the B6SJL-SOD1G93A ALS Mouse Model

Time-course and characterization of orolingual motor deficits in B6SJL-Tg(SOD1-G93A)1Gur/J mice

Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis

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