Unknown

Dataset Information

0

Muscle pathology, limb strength, walking gait, respiratory function and neurological impairment establish disease progression in the p.N155K canine model of X-linked myotubular myopathy.


ABSTRACT: BACKGROUND:Loss-of-function mutations in the myotubularin (MTM1) gene cause X-linked myotubular myopathy (XLMTM), a fatal, inherited pediatric disease that affects the entire skeletal musculature. Labrador retriever dogs carrying an MTM1 missense mutation exhibit strongly reduced synthesis of myotubularin, the founder member of a lipid phosphatase required for normal skeletal muscle function. The resulting canine phenotype resembles that of human patients with comparably severe mutations, and survival does not normally exceed 4 months. METHODS:We studied MTM1 mutant dogs (n=7) and their age-matched control littermates (n=6) between the ages of 10 and 25 weeks. Investigators blinded to the animal identities sequentially measured limb muscle pathology, fore- and hind limb strength, walking gait, respiratory function and neurological impairment. RESULTS:MTM1-mutant puppies display centrally-nucleated myofibers of reduced size and disrupted sarcotubular architecture progressing until the end of life, an average of 17 weeks. In-life measures of fore- and hind limb strength establish the rate at which XLMTM muscles weaken, and their corresponding decrease in gait velocity and stride length. Pulmonary function tests in affected dogs reveal a right-shifted relationship between peak inspiratory flow (PIF) and inspiratory time (TI); neurological assessments indicate that affected puppies as young as 10 weeks show early signs of neurological impairment (neurological severity score, NSS =8.6±0.9) with progressive decline (NSS =5.6±1.7 at 17 weeks-of-age). CONCLUSIONS:Our findings document the rate of disease progression in a large animal model of XLMTM and lay a foundation for preclinical studies.

SUBMITTER: Goddard MA 

PROVIDER: S-EPMC4630545 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

altmetric image

Publications

Muscle pathology, limb strength, walking gait, respiratory function and neurological impairment establish disease progression in the p.N155K canine model of X-linked myotubular myopathy.

Goddard Melissa A MA   Mack David L DL   Czerniecki Stefan M SM   Kelly Valerie E VE   Snyder Jessica M JM   Grange Robert W RW   Lawlor Michael W MW   Smith Barbara K BK   Beggs Alan H AH   Childers Martin K MK  

Annals of translational medicine 20151001 18


<h4>Background</h4>Loss-of-function mutations in the myotubularin (MTM1) gene cause X-linked myotubular myopathy (XLMTM), a fatal, inherited pediatric disease that affects the entire skeletal musculature. Labrador retriever dogs carrying an MTM1 missense mutation exhibit strongly reduced synthesis of myotubularin, the founder member of a lipid phosphatase required for normal skeletal muscle function. The resulting canine phenotype resembles that of human patients with comparably severe mutations  ...[more]

Similar Datasets

| S-EPMC4253544 | biostudies-literature
| S-EPMC4574743 | biostudies-literature
| S-EPMC2572588 | biostudies-literature
| S-EPMC4765322 | biostudies-literature
| S-EPMC5620115 | biostudies-literature
| S-EPMC7983207 | biostudies-literature
| S-EPMC4105197 | biostudies-literature
| S-EPMC10010109 | biostudies-literature
| S-EPMC3605830 | biostudies-other
| S-EPMC7000997 | biostudies-literature