title: Loss of dystrophin causes aberrant mechanotransduction in skeletal muscle fibers.
abstract: Dystrophin is a cytoskeletal protein found at the inner surface of skeletal and cardiac muscle fibers. We hypothesize that deficiency of dystrophin increases muscle compliance and causes an aberrant mechanotransduction in muscle fibers. To test this hypothesis, we measured the length-tension relationships and determined intracellular signaling leading to the activation of mitogen-activated protein (MAP) kinases in diaphragm muscle fibers from dystrophin-deficient mdx mice. Compared with controls, length-tension curves of the mdx mice were shifted to the right. A higher level of activation of extracellular signal-regulated kinase 1/2 (ERK1/2) but not c-Jun N-terminal kinase-1 or p38 MAP kinase was observed in the mdx muscle compared with the normal muscle in response to mechanical stretch. Removal of Ca2+ from the medium inhibited stretch-induced ERK1/2 activation only in mdx muscle fibers but not in the normal fibers. Conversely, pretreatment with TMB-8 (an antagonist of intracellular Ca2+ blocked the mechanical stretch-induced ERK1/2 activation in normal but not in mdx muscle fibers. Pretreatment of muscle with nifedipine (L-type calcium channel antagonist) marginally decreased the activation of ERK1/2 in normal or mdx muscle whereas pretreatment with gadolinium (III) chloride (an inhibitor of stretch-activated channels) only blocked the activation of ERK1/2 in mdx muscle, with no significant effect on normal muscle. A higher basal level of activation of activator protein-1 (AP-1) transcription factor was observed in dystrophin-deficient diaphragm, which was further augmented by mechanical stretch. Mechanical stretch-induced activation of AP-1 was decreased by pretreatment of muscle fibers with PD98059 (ERK1/2 inhibitor) and removal of Ca2+ ions from incubation medium. Our results show that dystrophin is a load-bearing element and its deficiency leads to loss of muscle stiffness and aberrant mechanotransduction in skeletal muscle fibers.
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.forename: Niraj
authors.initials: N
authors.lastname: Khandelwal
authors.forename: Rahul
authors.initials: R
authors.lastname: Malya
authors.forename: Michael B
authors.initials: MB
authors.lastname: Reid
authors.forename: Aladin M
authors.initials: AM
authors.lastname: Boriek
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology; D046508:Culture Techniques; D016189:Dystrophin / Q000235:genetics / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D007473:Ion Channels / Q000502:physiology; D040542:Mechanotransduction, Cellular; D051379:Mice; D018101:Mice, Inbred mdx; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D013314:Stress, Mechanical; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D016189:Dystrophin; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007473:Ion Channels; D018808:Transcription Factor AP-1; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D002118:Calcium