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.

PTEN Contributes to Profound PI3K/Akt Signaling Pathway Deregulation in Dystrophin-Deficient Dog Muscle

“…[17][18][19][21][22][23] Nevertheless, these studies have generally focused on one protein rather than assessing the global changes that may precipitate or exacerbate the pathology. Moreover, they have been mainly performed in the mdx mouse, a model that most likely will exhibit species specific changes that may not be reflected in the course of the human disease.…”

“…[13][14][15] Moreover, studies of the X chromosome-linked muscular dystrophy (mdx) mouse 16 revealed modulations in mitogen-activated protein kinase (MAPK) signaling cascades, as dystrophic animals exhibited increased phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) 17,18 and c-jun N-terminal kinases 1 and 2 (JNK1/2), 19 -21 and decreased phosphorylation of p38. 18 Also, the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway has been shown to be affected in the mdx mouse, with increased synthesis and phosphorylation of Akt.…”

A Multidisciplinary Evaluation of the Effectiveness of Cyclosporine A in Dystrophic Mdx Mice

“…14,43,44 Another intriguing, although purely speculative, hypothesis to explain the CsA effectiveness in both DIA and EDL muscle is that the expression of functional chloride channel may be controlled by mechanosensitive mitogen-activated protein kinase (MAPK) cascades that are enhanced in dystrophin-deficient muscle fibers and also involves activation of calcineurin. 42,49,50 In fact this complex network of kinase/phosphatase pathways modulates different cellular targets either in a short term or through the modulation of gene expression, ie, by enhancing the transcription of inflammatory genes or controlling translational events of ion channels. 42,50,51 The CsA treatment did not ameliorate the alteration of calcium homeostasis that is a typical hallmark of dystrophic fibers and is worsened by exercise.…”

“…42,49,50 In fact this complex network of kinase/phosphatase pathways modulates different cellular targets either in a short term or through the modulation of gene expression, ie, by enhancing the transcription of inflammatory genes or controlling translational events of ion channels. 42,50,51 The CsA treatment did not ameliorate the alteration of calcium homeostasis that is a typical hallmark of dystrophic fibers and is worsened by exercise. 2,4,29 CsA per se may even lead to a further increase in calcium mobilization; 52 thus our finding leads to two main considerations: the first one is that the alteration in calcium homeostasis is rather independent on the inflammatory reaction.…”

Localized Treatment with a Novel FDA-Approved Proteasome Inhibitor Blocks the Degradation of Dystrophin and Dystrophin-Associated Proteins in mdx Mice

“…3 Dystrophin 4 is a peripheral membrane protein of ~426 kDa important for maintenance of muscle integrity, such that its deficiency results in the structural perturbation of the plasma membrane of skeletal muscle fibers. 5 Indeed, dystrophin associates with a large multimeric complex, termed the dystrophin-glycoprotein complex (DGC), including the dystroglycan complex (a and b-dystroglycan) and the sarcoglycan complex (a, b, g, d-sarcoglycan). 6 The consequence of loss of dystrophin is the absence or the great reduction of components of the DGC, as described for skeletal muscle fibers from DMD patients and from a mouse model of DMD, named the mdx mouse.…”