Preface

Skeletal muscle is a highly plastic organ that is modulated by various pathways controlling protein turnover. Loss of muscle is a serious consequence of many chronic diseases and of aging. Muscle loss is also common in muscular dystrophy, in which marked loss of various proteins such as the dystrophin–glycoprotein complex occurs around muscle fibers. The autophagy-dependent system and ubiquitin– proteasome signaling (UPS) are well known as major intracellular degradation systems, and their 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 protein content, muscle fiber size, and muscle strength. The apparent defect of autophagy-dependent signaling is observed in various muscular dystrophies. The adaptive changes of UPS are highly controversial in Duchenne muscular dystrophy (DMD), limb-girdle muscular dystrophy, and Ullrich congenital muscular dystrophy.

Many researchers have investigated exercise-based, supplemental, pharmacological, gene therapy approaches to attenuate various muscular dystrophies. 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 very difficult for obtaining positive effects and there are few possibilities of its clinical application. Glucocorticoids (GCs) are commonly used and still serve as a gold standard therapy. Nowadays, weekly, intermittent GC treatment has been shown to provide a better alternative to a daily regimen. More recently, attention has been paid to induced pluripotent stem cell technology and its potential application in DMD treatment, although almost all studies use DMD model mdx mice. In addition, the strategy using CRISPR/Cas9 technology progressed dramatically for the restoration of functional dystrophin. An increasing number of studies report successful and beneficial effects of CRISPR/ Cas9 only animal models of muscular dystrophy. Thus, it seems necessary that genome editing tools be applied the dystrophic patients for some time to come.

This book provides a comprehensive overview of the various muscular dystrophies, including characteristics, diagnosis, and classification. General treatment of drugs (e.g. corticosteroids) and physical therapy for muscular dystrophies are discussed. In addition, current applications for cell and tissue engineering using muscle stem cells or gene therapy are introduced. This book also deals with the recent advances in appropriate models of drug screening using cell cultures or mammalian organs in vitro in this field.

**II**

**Chapter 7 89**

The Muscular Dystrophy Model **101**

**Chapter 8 103**

Pharmacological Actions and Potential Therapeutic Use of Cannabinoids in

Interspecies Translation: Bovine Marbling to Human Muscular Dystrophy *by Jose L. Valenzuela, Sally S. Lloyd, Edward J. Steele, Francis L. Mastaglia* 

Duchenne's Muscular Dystrophy

*by Fabio Arturo Iannotti*

*and Roger L. Dawkins*

**Section 5**

**Kunihiro Sakuma** Professor Tokyo Institute of Technology, Tokyo, Japan

**1**

Section 1

Introduction

Section 1 Introduction

**3**

**Chapter 1**

Strategy

**1. Introduction**

*Kunihiro Sakuma*

Introductory Chapter: Muscular

Dystrophy and Recent Therapeutic

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

Nowadays, the autophagy-dependent system and ubiquitin-proteasome signal-

ing (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

important cause of different muscular dystrophy.

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
