Direct observation of failing fibers in muscles of dystrophic mice provides mechanistic insight into muscular dystrophy

• Published in: American Journal of Physiology: Cell Physiology 2008-02, Vol.294 (2), p.C651-C658
• Main Authors: Claflin, Dennis R, Brooks, Susan V
• Format: Article
• Language: English
• Subjects: Animals; Biochemistry; Calcium; Calcium - metabolism; Calcium Signaling - physiology; Cytoplasm - metabolism; Cytoskeleton - genetics; Cytoskeleton - metabolism; Cytoskeleton - ultrastructure; Disease Models, Animal; Disease Progression; Dystrophin - genetics; Extracellular Fluid - metabolism; Mice; Mice, Inbred C57BL; Mice, Inbred mdx; Muscle Contraction - genetics; Muscle Fibers, Skeletal - metabolism; Muscle Fibers, Skeletal - pathology; Muscle Strength - genetics; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscle, Skeletal - physiopathology; Muscular dystrophy; Muscular Dystrophy, Animal - metabolism; Muscular Dystrophy, Animal - pathology; Muscular Dystrophy, Animal - physiopathology; Muscular Dystrophy, Duchenne - metabolism; Muscular Dystrophy, Duchenne - pathology; Muscular Dystrophy, Duchenne - physiopathology; Musculoskeletal system; Proteins; Rodents; Sarcolemma - metabolism; Sarcolemma - ultrastructure; Sarcoplasmic Reticulum - metabolism; Sarcoplasmic Reticulum - ultrastructure; Stress, Mechanical
• ISSN: 0363-6143; 1522-1563
• DOI: 10.1152/ajpcell.00244.2007

1 Department of Surgery, Section of Plastic Surgery and 2 Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan Submitted 8 June 2007 ; accepted in final form 27 December 2007 Duchenne muscular dystrophy is caused by the absence of the protein dystrophin. Dystrophin's function is not known, but its cellular location and associations with both the force-generating contractile core and membrane-spanning entities suggest a role in mechanically coupling force from its intracellular origins to the fiber membrane and beyond. We report here the presence of destructive contractile activity in lumbrical muscles from dystrophin-deficient ( mdx ) mice during nominally quiescent periods following exposure to mechanical stress. The ectopic activity, which was observable microscopically, resulted in longitudinal separation and clotting of fiber myoplasm and was absent when calcium (Ca 2+ ) was removed from the bathing medium. Separation and clotting of myoplasm were also produced in dystrophin-deficient muscles by local application of a Ca 2+ ionophore to create membrane breaches in the absence of mechanical stress, whereas muscles from control mice tolerated ionophore-induced entry of Ca 2+ without damage. These observations suggest a failure cascade in dystrophin-deficient fibers that 1 ) is initiated by a stress-induced influx of extracellular Ca 2+ , causing localized activation to continue after cessation of stimulation, and 2 ) proceeds as the persistent local activation, combined with reduced lateral mechanical coupling between the contractile core and the extracellular matrix, results in longitudinal separation of myoplasm in nonactivated regions of the fiber. This mechanism invokes both the membrane stabilization and the mechanical coupling functions frequently proposed for dystrophin and suggests that, whereas the absence of either function alone is not sufficient to cause fiber failure, their combined absence is catastrophic. skeletal muscle; muscle damage; dystrophin Address for reprint requests and other correspondence: D. R. Claflin, Univ. of Michigan, BSRB, Rm. 2027, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200 (e-mail: claflin{at}umich.edu )