当前位置： SCI文献检索 > PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA期刊下所有文献 > Physical exertion exacerbates decline in the musculature of an animal model of Duchenne muscular dystrophy.

Physical exertion exacerbates decline in the musculature of an animal model of Duchenne muscular dystrophy.

Abstract：

:Duchenne muscular dystrophy (DMD) is a genetic disorder caused by loss of the protein dystrophin. In humans, DMD has early onset, causes developmental delays, muscle necrosis, loss of ambulation, and death. Current animal models have been challenged by their inability to model the early onset and severity of the disease. It remains unresolved whether increased sarcoplasmic calcium observed in dystrophic muscles follows or leads the mechanical insults caused by the muscle's disrupted contractile machinery. This knowledge has important implications for patients, as potential physiotherapeutic treatments may either help or exacerbate symptoms, depending on how dystrophic muscles differ from healthy ones. Recently we showed how burrowing dystrophic (dys-1) C. elegans recapitulate many salient phenotypes of DMD, including loss of mobility and muscle necrosis. Here, we report that dys-1 worms display early pathogenesis, including dysregulated sarcoplasmic calcium and increased lethality. Sarcoplasmic calcium dysregulation in dys-1 worms precedes overt structural phenotypes (e.g., mitochondrial, and contractile machinery damage) and can be mitigated by reducing calmodulin expression. To learn how dystrophic musculature responds to altered physical activity, we cultivated dys-1 animals in environments requiring high intensity or high frequency of muscle exertion during locomotion. We find that several muscular parameters (e.g., size) improve with increased activity. However, longevity in dystrophic animals was negatively associated with muscular exertion, regardless of effort duration. The high degree of phenotypic conservation between dystrophic worms and humans provides a unique opportunity to gain insight into the pathology of the disease as well as the initial assessment of potential treatment strategies.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Hughes KJ,Rodriguez A,Flatt KM,Ray S,Schuler A,Rodemoyer B,Veerappan V,Cuciarone K,Kullman A,Lim C,Gutta N,Vemuri S,Andriulis V,Niswonger D,Barickman L,Stein W,Singhvi A,Schroeder NE,Vidal-Gadea AG

doi

10.1073/pnas.1811379116

subject

Has Abstract

pub_date

2019-02-26 00:00:00

pages

3508-3517

issue

eissn

0027-8424

issn

1091-6490

pii

1811379116

journal_volume

116

pub_type

杂志文章

在线工具

Physical exertion exacerbates decline in the musculature of an animal model of Duchenne muscular dystrophy.