Identification of FHL1 as a therapeutic target for Duchenne muscular dystrophy

D’Arcy, Colleen; Feeney, Sandra J.; McLean, Catriona; Gehrig, Stefan M.; Lynch, Gordon S.; Smith, Jaclyn E.; Cowling, Belinda S.; Mitchell, Christina A.; Mcgrath, Meagan Jane

doi:10.1093/hmg/ddt449

Cited by 13 publications

(10 citation statements)

References 60 publications

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“…Dysregulation of FHL1 due to mutations in this protein are causative for several forms of human X-linked skeletal muscle dystrophies: Emery-Dreifuss muscular dystrophy, reducing body myopathy, rigid spine syndrome, scapuloperoneal myopathy, and X-linked myopathy with postural muscle atrophy [reviewed in (126)]. FHL1 upregulation is potentially therapeutic for skeletal myopathies as upregulation can rescue a DMD mouse model ( mdx model) by increasing muscle hypertrophy through the NFAT pathway (136). Furthermore, upregulation of FHL1 is detected at early stages of DCM progression in multiple mouse models, making it a promising candidate as a marker of early detection of DCM (195).…”

Section: Sarcomere—the Basic Contractile Unit Of Striated Musclementioning

confidence: 99%

Overview of the Muscle Cytoskeleton

Henderson

Gomez

Novak

et al. 2017

Comprehensive Physiology

222

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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Section: Sarcomere—the Basic Contractile Unit Of Striated Musclementioning

confidence: 99%

Overview of the Muscle Cytoskeleton

Henderson

Gomez

Novak

et al. 2017

Comprehensive Physiology

222

193

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“…Furthermore, a systemic strategy designed to increase the endogenous utrophin level to treat all skeletal muscle (including the diaphragm) and heart, would not be anticipated to result in an immune response ( 25 ). To date, direct delivery of the protein ( 35 ) or stabilization of the protein or RNA ( 36 , 37 ), viral approaches ( 38 , 39 ), non-viral strategies such as recombinant biglycan ( 40 ) and oral compound administration designed to modulate the utrophin expression at the transcriptional level ( 41 , 42 ), showed that maintaining utrophin expression in mdx muscle fibres could decrease the progression of the disease and represents a promising therapeutic avenue for DMD.…”

Section: Introductionmentioning

confidence: 99%

Second-generation compound for the modulation of utrophin in the therapy of DMD

et al. 2015

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Duchenne muscular dystrophy (DMD) is a lethal, X-linked muscle-wasting disease caused by lack of the cytoskeletal protein dystrophin. There is currently no cure for DMD although various promising approaches are progressing through human clinical trials. By pharmacologically modulating the expression of the dystrophin-related protein utrophin, we have previously demonstrated in dystrophin-deficient mdx studies, daily SMT C1100 treatment significantly reduced muscle degeneration leading to improved muscle function. This manuscript describes the significant disease modifying benefits associated with daily dosing of SMT022357, a second-generation compound in this drug series with improved physicochemical properties and a more robust metabolism profile. These studies in the mdx mouse demonstrate that oral administration of SMT022357 leads to increased utrophin expression in skeletal, respiratory and cardiac muscles. Significantly, utrophin expression is localized along the length of the muscle fibre, not just at the synapse, and is fibre-type independent, suggesting that drug treatment is modulating utrophin transcription in extra-synaptic myonuclei. This results in improved sarcolemmal stability and prevents dystrophic pathology through a significant reduction of regeneration, necrosis and fibrosis. All these improvements combine to protect the mdx muscle from contraction induced damage and enhance physiological function. This detailed evaluation of the SMT C1100 drug series strongly endorses the therapeutic potential of utrophin modulation as a disease modifying therapeutic strategy for all DMD patients irrespective of their dystrophin mutation.

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“…The myosin isoform MHY7, which was induced by more than 10 fold by tadalafil treatment, is also implicated in cardiac hypertrophy. Other hypertrophic markers such as the transcript variant four of PGC‐1α (PGC‐1α‐4; Ruas et al, ), FHL‐1 D'Arcy et al, ) and IGF‐1 were found to be overexpressed in dystrophic muscles following tadalafil treatment (Fig. ).…”

Section: Resultsmentioning

confidence: 95%

Pathways Implicated in Tadalafil Amelioration of Duchenne Muscular Dystrophy

Arcangelis

Strimpakos

Gabanella

et al. 2015

Journal Cellular Physiology

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Numerous therapeutic approaches for Duchenne and Becker Muscular Dystrophy (DMD and BMD), the most common X-linked muscle degenerative disease, have been proposed. So far, the only one showing a clear beneficial effect is the use of corticosteroids. Recent evidence indicates an improvement of dystrophic cardiac and skeletal muscles in the presence of sustained cGMP levels secondary to a blocking of their degradation by phosphodiesterase five (PDE5). Due to these data, we performed a study to investigate the effect of the specific PDE5 inhibitor, tadalafil, on dystrophic skeletal muscle function. Chronic pharmacological treatment with tadalafil has been carried out in mdx mice. Behavioral and physiological tests, as well as histological and biochemical analyses, confirmed the efficacy of the therapy. We then performed a microarray-based genomic analysis to assess the pattern of gene expression in muscle samples obtained from the different cohorts of animals treated with tadalafil. This scrutiny allowed us to identify several classes of modulated genes. Our results show that PDE5 inhibition can ameliorate dystrophy by acting at different levels. Tadalafil can lead to (1) increased lipid metabolism; (2) a switch towards slow oxidative fibers driven by the up-regulation of PGC-1α; (3) an increased protein synthesis efficiency; (4) a better actin network organization at Z-disk.

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Identification of FHL1 as a therapeutic target for Duchenne muscular dystrophy

Cited by 13 publications

References 60 publications

Overview of the Muscle Cytoskeleton

Overview of the Muscle Cytoskeleton

Second-generation compound for the modulation of utrophin in the therapy of DMD

Pathways Implicated in Tadalafil Amelioration of Duchenne Muscular Dystrophy

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