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Introductory Chapter: Muscular Dystrophy and Recent Therapeutic Strategy

Written By

Kunihiro Sakuma

Submitted: 14 March 2019 Published: 02 October 2019

DOI: 10.5772/intechopen.86709

From the Edited Volume

Muscular Dystrophies

Edited by Kunihiro Sakuma

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1. Introduction

Skeletal muscle tissue accounts for almost half of the human body mass. Human health is markedly affected by any deterioration in the material, metabolic, and contractile properties of skeletal muscle. Skeletal muscle is a highly plastic organ that is modulated by various pathways controlling cell and protein turnover.

Loss of muscle is a serious consequence of many chronic diseases and of aging itself. Muscle loss is also common in muscular dystrophy, in which marked loss of various membranous structural proteins occurs around muscle fibers [1]. Defects in components of the dystrophin-glycoprotein complex (DGC) are known to be an important cause of different muscular dystrophy.

Nowadays, the autophagy-dependent system and ubiquitin-proteasome signaling (UPS) are well known as a major intracellular degradation system, and its appropriate function is crucial to health and muscle homeostasis. Indeed, muscle wasting and weakness such as cachexia, dystrophy, and sarcopenia is characterized by marked decreases in the protein content, muscle fiber size, and muscle strength. Interestingly, a functional defect in autophagy-dependent signaling in sarcopenic mice and humans was recently suggested [2, 3]. In addition, apparent defect of autophagy-dependent signaling is also observed in various muscular dystrophies. Indeed, De Palma et al. [4] have described marked defect of autophagy in dystrophin-deficient mdx mice and Duchenne muscular dystrophy (DMD) patients through the electron microscopic evaluation of muscle tissue and decreased autophagic regulator proteins (i.e., Bnip3, Atg12, and LC3-II). The adaptive changes of UPS are highly controversial in several muscular dystrophies such as DMD, LGMD, and Ullrich congenital muscular dystrophy [5], although UPS seems to not be activated in human sarcopenic muscle [6].


2. Various therapeutic approaches for muscle dystrophy

To attenuate various forms of muscular dystrophy, many researchers have investigated exercise-based, supplemental, pharmacological, and gene therapy approaches. Currently, there is no cure for patients suffering from muscular dystrophies. Although several researchers actively try to determine the effect of pharmacological inhibition of myostatin for DMD patients, it is heavily difficult to obtain positive effects and there are few possibilities for clinical application. Indeed, a randomized clinical trial of anti-myostatin for DMD patients had a trend toward improved muscle mass and performance, but was stopped early due to non-muscle side effects (i.e., epistaxis and telangiectasias) [7]. Glucocorticoids (GCs) are commonly used and still serve as a gold standard therapy, acting as anti-inflammatory drugs [8]. More recently, weekly, intermittent GCs treatment has been shown to provide a better alternative to a daily regimen without eliciting muscle atrophy [9]. Recently, more attention is paid to induced pluripotent stem cells (iPSCs) technology and their potential application in DMD treatment [10], although almost all studies used DMD model mdx mice. In addition, the strategy using CRISPR/Cas9 technology progressed dramatically for the restoration of functional dystrophin [11]. Young et al. [12] have found that removal of exons 45–55 resulted in the expression of the stable dystrophin protein in both cardiomyocytes and skeletal myotube in vitro. An increasing number of studies report successful and beneficial effects of CRISPR/Cas9 only animal models of muscular dystrophy. Thus, it seems to be necessary for substantial time for genome editing tools to apply the dystrophic patients.


  1. 1. Vainzof M, Ayub-Guerrieri D, Onofre PC, Martins PC, Lopes VF, Zilberztajn D, et al. Animal models for genetic neuromuscular disease. Journal of Molecular Neuroscience. 2008;34(3):241-248
  2. 2. Carnio S, LoVerso F, Baraibar MA, Longa E, Khan MM, Maffei M, et al. Autophagy impairment in muscle induces neuromuscular junction degeneration and precocious aging. Cell Reports. 2014;8(5):1509-1521
  3. 3. Sakuma K, Kinoshita M, Ito Y, Aizawa M, Aoi W, Yamaguchi A. p62/SQSTM1 but not LC3 is accumulated in sarcopenic muscle of mice. Journal of Cachexia, Sarcopenia and Muscle. 2016;7(2):204-212
  4. 4. De Palma C, Morisi F, Cheli S, Pambianco S, Cappello V, Vezzoli M, et al. Autophagy as a new therapeutic target in Duchenne muscular dystrophy. Cell Death & Disease. 2012;3:e418
  5. 5. Sakuma K, Aoi W, Yamaguchi A. The intriguing regulators of muscle mass in sarcopenia and muscular dystrophy. Frontiers in Aging Neuroscience. 2013;6:230
  6. 6. Sakuma K, Aoi W, Yamaguchi A. Molecular mechanism of sarcopenia and cachexia: Recent research advances. Pflügers Archiv/European Journal of Physiology. 2017;469(5-6):573-591
  7. 7. Campbell C, McMillan HJ, Mah JK, Tarnopolsky M, Selby K, McClure T, et al. Myostatin inhibitor ACE-031 treatment of ambulatory boys with Duchenne muscular dystrophy: Results of a randomized, placebo-controlled clinical trial. Muscle & Nerve. 2017;55(4):458-464
  8. 8. Ciafaloni E, Moxley RT. Treatment options for Duchenne muscular dystrophy. Current Treatment Options in Neurology. 2008;10(2):86-93
  9. 9. Quattrocelli M, Barefield DY, Warner JL, Vo AH, Hadhazy M, Earley JU, et al. Intermittent glucocorticoid steroid dosing ehnahces muscle repair without eliciting muscle atrophy. Journal of Clinical Investigation. 2017;127(6):2418-2432
  10. 10. Kalra S, Montanaro F, Denning C. Can human pluripotent stem cell-derived cardiomyocytes advances understanding of muscular sydtrophies? Journal of Neuromuscular Diseases. 2016;3(3):309-332
  11. 11. Salmaninejad A, Valilou SF, Bayat H, Ebadi N, Daraei A, Yousefi M, et al. Duchenne muscular dystrophy: An updated review of common available therapies. The International Journal of Neuroscience. 2018;128(9):854-864
  12. 12. Young CS, Hicks MR, Ermolova NV, Nakano H, Jan M, Younesi S, et al. A single CRISPR-Cas9 deletion strategy that targets the majority of DMD patients restores dystrophin function in hipsC-derived muscle cells. Cell Stem Cell. 2016;18(4):533-540

Written By

Kunihiro Sakuma

Submitted: 14 March 2019 Published: 02 October 2019