Molecular, cellular, and muscle strip mechanics of the <i>mdx</i> mouse diaphragm

Bates, Genevieve; Sigurdardottir, Sara; Kachmar, Linda; Zitouni, Nedjma B.; Benedetti, Andrea; Petrof, Basil J.; Rassier, Dilson E.; Lauzon, Anne‐Marie

doi:10.1152/ajpcell.00220.2012

Cited by 13 publications

(25 citation statements)

References 45 publications

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“…Dystrophic diaphragm muscle undergoes repetitive cycles of degeneration and regeneration, with additional activation of inflammatory cascades that further exacerbate muscle weakness. Although diaphragm muscle function has been well characterized in DMD (De Bruin et al 1997) and the mdx mouse (Coirault et al 1999(Coirault et al , 2003Bates et al 2013), little is known about the complementary muscles of breathing, especially the airway dilator muscles of the pharynx that are crucial in the control of airway calibre, which is surprising given the prevalence of sleep-disordered breathing in DMD boys (Bersanini et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Restoration of pharyngeal dilator muscle force in dystrophin‐deficient (mdx) mice following co‐treatment with neutralizing interleukin‐6 receptor antibodies and urocortin 2

Burns

Rowland

Canavan

et al. 2017

Experimental Physiology

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What is the central question of this study? We previously reported impaired upper airway dilator muscle function in the mdx mouse model of Duchenne muscular dystrophy (DMD). Our aim was to assess the effect of blocking interleukin-6 receptor signalling and stimulating corticotrophin-releasing factor receptor 2 signalling on mdx sternohyoid muscle structure and function. What is the main finding and its importance? The interventional treatment had a positive inotropic effect on sternohyoid muscle force, restoring mechanical work and power to wild-type values, reduced myofibre central nucleation and preserved the myosin heavy chain type IIb fibre complement of mdx sternohyoid muscle. These data might have implications for development of pharmacotherapies for DMD with relevance to respiratory muscle performance. The mdx mouse model of Duchenne muscular dystrophy shows evidence of impaired pharyngeal dilator muscle function. We hypothesized that inflammatory and stress-related factors are implicated in airway dilator muscle dysfunction. Six-week-old mdx (n = 26) and wild-type (WT; n = 26) mice received either saline (0.9% w/v) or a co-administration of neutralizing interleukin-6 receptor antibodies (0.2 mg kg ) and corticotrophin-releasing factor receptor 2 agonist (urocortin 2; 30 μg kg ) over 2 weeks. Sternohyoid muscle isometric and isotonic contractile function was examined ex vivo. Muscle fibre centronucleation and muscle cellular infiltration, collagen content, fibre-type distribution and fibre cross-sectional area were determined by histology and immunofluorescence. Muscle chemokine content was examined by use of a multiplex assay. Sternohyoid peak specific force at 100 Hz was significantly reduced in mdx compared with WT. Drug treatment completely restored force in mdx sternohyoid to WT levels. The percentage of centrally nucleated muscle fibres was significantly increased in mdx, and this was partly ameliorated after drug treatment. The areal density of infiltrates and collagen content were significantly increased in mdx sternohyoid; both indices were unaffected by drug treatment. The abundance of myosin heavy chain type IIb fibres was significantly decreased in mdx sternohyoid; drug treatment preserved myosin heavy chain type IIb complement in mdx muscle. The chemokines macrophage inflammatory protein 2, interferon-γ-induced protein 10 and macrophage inflammatory protein 3α were significantly increased in mdx sternohyoid compared with WT. Drug treatment significantly increased chemokine expression in mdx but not WT sternohyoid. Recovery of contractile function was impressive in our study, with implications for Duchenne muscular dystrophy. The precise molecular mechanisms by which the drug treatment exerts an inotropic effect on mdx sternohyoid muscle remain to be elucidated.

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Section: Discussionmentioning

confidence: 99%

Restoration of pharyngeal dilator muscle force in dystrophin‐deficient (mdx) mice following co‐treatment with neutralizing interleukin‐6 receptor antibodies and urocortin 2

Burns

Rowland

Canavan

et al. 2017

Experimental Physiology

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“…Mice exhibit pseudo-hypertrophy (muscle is enlarged because it is replaced with connective tissue and fat) in several skeletal muscle types (39,479,548). The fibrosis and force reduction in the thoracic diaphragm relates closely to the human disease, though less severe (49,200,218,278,653). In both humans and mice utrophin is upregulated in dystrophin-deficient muscle but, unlike in humans, this upregulation partially rescues the dystrophic phenotype in mdx mice (207).…”

Section: The Costamere: Protects Against Mechanical Stress and Is An mentioning

confidence: 99%

Overview of the Muscle Cytoskeleton

Henderson

Gomez

Novak

et al. 2017

Comprehensive Physiology

235

193

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Cardiac and skeletal striated muscles are intricately designed machines responsible for muscle contraction. Coordination of the basic contractile unit, the sarcomere, and the complex cytoskeletal networks are critical for contractile activity. The sarcomere is comprised of precisely organized individual filament systems that include thin (actin), thick (myosin), titin, and nebulin. Connecting the sarcomere to other organelles (e.g., mitochondria and nucleus) and serving as the scaffold to maintain cellular integrity are the intermediate filaments. The costamere, on the other hand, tethers the sarcomere to the cell membrane. Unique structures like the intercalated disc in cardiac muscle and the myotendinous junction in skeletal muscle help synchronize and transmit force. Intense investigation has been done on many of the proteins that make up these cytoskeletal assemblies. Yet the details of their function and how they interconnect have just started to be elucidated. A vast number of human myopathies are contributed to mutations in muscle proteins; thus understanding their basic function provides a mechanistic understanding of muscle disorders. In this review, we highlight the components of striated muscle with respect to their interactions, signaling pathways, functions, and connections to disease.

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“…2011; Bates et al . 2013), but there is clearly a disruption of the ECM. Many fibrotic diseases are associated with increased tissue stiffness – an important predictor of disease progression in liver fibrosis (Georges et al .…”

Section: Introductionmentioning

confidence: 98%

Passive stiffness of fibrotic skeletal muscle in mdx mice relates to collagen architecture

Brashear

Wohlgemuth

Gonzalez

et al. 2020

The Journal of Physiology

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Key points The amount of fibrotic material in dystrophic mouse muscles relates to contractile function, but not passive function. Collagen fibres in skeletal muscle are associated with increased passive muscle stiffness in fibrotic muscles. The alignment of collagen is independently associated with passive stiffness in dystrophic skeletal muscles. These outcomes demonstrate that collagen architecture rather than collagen content should be a target of anti‐fibrotic therapies to treat muscle stiffness. Abstract Fibrosis is prominent in many skeletal muscle pathologies including dystrophies, neurological disorders, cachexia, chronic kidney disease, sarcopenia and metabolic disorders. Fibrosis in muscle is associated with decreased contractile forces and increased passive stiffness that limits joint mobility leading to contractures. However, the assumption that more fibrotic material is directly related to decreased function has not held true. Here we utilize novel measurement of extracellular matrix (ECM) and collagen architecture to relate ECM form to muscle function. We used mdx mice, a model for Duchenne muscular dystrophy that becomes fibrotic, and wildtype mice. In this model, extensor digitorum longus (EDL) muscle was significantly stiffer, but with similar total collagen, while the soleus muscle did not change stiffness, but increased collagen. The stiffness of the EDL was associated with increased collagen crosslinking as determined by collagen solubility. Measurement of ECM alignment using polarized light microscopy showed a robust relationship between stiffness and alignment for wildtype muscle that broke down in mdx muscles. Direct visualization of large collagen fibres with second harmonic generation imaging revealed their relative abundance in stiff muscles. Collagen fibre alignment was linked to stiffness across all muscles investigated and the most significant factor in a multiple linear regression‐based model of muscle stiffness from ECM parameters. This work establishes novel characteristics of skeletal muscle ECM architecture and provides evidence for a mechanical function of collagen fibres in muscle. This finding suggests that anti‐fibrotic strategies to enhance muscle function and excessive stiffness should target large collagen fibres and their alignment rather than total collagen.

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Molecular, cellular, and muscle strip mechanics of the mdx mouse diaphragm

Abstract: A, Petrof BJ, Rassier D, Lauzon AM. Molecular, cellular, and muscle strip mechanics of the mdx mouse diaphragm.

Cited by 13 publications

References 45 publications

Restoration of pharyngeal dilator muscle force in dystrophin‐deficient (mdx) mice following co‐treatment with neutralizing interleukin‐6 receptor antibodies and urocortin 2

Restoration of pharyngeal dilator muscle force in dystrophin‐deficient (mdx) mice following co‐treatment with neutralizing interleukin‐6 receptor antibodies and urocortin 2

Overview of the Muscle Cytoskeleton

Passive stiffness of fibrotic skeletal muscle in mdx mice relates to collagen architecture

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