Introductory Chapter: Skeletal Muscle Disorders – Emerging New Avenues for the Diagnosis and Treatment

1. Introduction

After years of intense clinical and experimental research using structural, biological, and biochemical experimental procedures, it is clear that the etiology and severity of skeletal muscle disorders, which encompass a large and complex heterogeneous group of diseases known as myopathies, are determined by a complex relationship between genetic and environmental factors and not last by multiple organ dysfunctions. Myopathies generally are grouped into two main categories: acquired and genetically determined (hereditary). All of them have a rare or extremely rare frequency. This often makes difficult the final diagnosis and development of a treatment leading to an inadequate response to the needs of patients and their families.

2. Current and promising therapeutic options for muscular dystrophies

Included in the acquired group of muscle disorders are endocrine, metabolic, inflammatory (polymyositis, dermatomyositis, and inclusion body myositis) and toxic myopathies. While hereditary myopathies include congenital, metabolic, mitochondrial, myotonias, and muscular dystrophies that are caused by mutations in different genes-encoding proteins that play important roles in muscle structure and function with X-linked, autosomal-recessive, or autosomal-dominant inheritance patterns. Among them, Duchenne (DMD) and Becker (BMD) muscular dystrophies are the most frequent whose prevalence is estimated at 4.8 per 100,000 people (95 CI 3.6–6.3 per 100,000 people) and 1.6 per 100,000 people (95 CI 1.1–2.4 per 100,000 people), respectively [1]. Other forms of inherited myopathies (extremely rare) include sarcoglicanopathies, and congenital and metabolic myopathies. The progressive irreversible loss of muscle fibers resulting from repetitive cycles of degeneration, necrosis, regeneration, and eventually fibrosis and fat is a common pathological event of muscular dystrophies.

Unfortunately, a cure for DMD as well as other muscular dystrophies is not available, although innovative experimental therapies such as gene therapy, CRISPR/Cas9, exon-skipping, cell therapy have made astonishing advances over the years [2]. As a consequence, the use of anti-inflammatory drugs mostly including steroids remains the mainstay of palliative care. In particular, prednisolone (PRED) and deflazacort (DFZ) were shown to produce the beneficial effects on the preservation of functional abilities in several mouse models of DMD and randomized controlled trials [3, 4]. However, the long-term daily use of corticosteroids may cause in young boys metabolic and growth-related side effects, pubertal delay, and increased risk of vertebral fractures [5, 6]. But why do novel therapies achieve limited success? Undoubtedly, introducing changes into specific cells of the body by targeting a specific gene or part of it is feasible but often challenging, especially in skeletal muscle cells/tissues that are extremely vast accounting in fact for almost half of the human body mass. Moreover, the success of experimental therapies is limited by the complex structure of skeletal muscles organized in numerous bundles of muscle fiber (myofibers) containing millions of myofibrils. Not least, the type of muscles affected by the disease may vary with the type of hereditary disorder [7]. Besides skeletal muscles, cardiac problems in hereditary muscle diseases are frequent and include cardiomyopathies, defects of cardiac conductions with or without primary myocardial muscle involvement, and arrhythmias [8]. Remarkably, there is also evidence of central nervous system involvement in skeletal muscle disorders [9]. In this respect, progresses in neuroimaging and electrophysiological techniques demonstrated that the absence or reduced expression of dystrophin leads to neurological, cognitive, and neuroanatomical alterations to varying degrees of severity in a significant number of DMD patients [10]. However, the current knowledge about the molecular mechanisms underlying behavioral and cognitive deficits in DMD patients remains very modest [11]. The most accredited hypothesis is that the loss of dystrophin causes a displacement of key proteins at the synaptic level with consequent disruptions of their functions [10]. Consequently, the production of pro-inflammatory cytokines contributes to memory defects and neurochemical alterations [12]. In both animal models and patients with DMD, an increase in pro-inflammatory factors including interleukin 6 (IL-6), interleukin 1β (IL-1β), and tumor necrosis factor-α (TNF-α) was found in muscle tissues as well as blood samples [13, 14]. Furthermore, Nico and colleagues showed that mdx mice, a validated animal model of DMD, present an increase in blood-brain barrier permeability associated with an increased matrix-metalloproteinase-2 and matrix-metalloproteinase-9 expression. These changes may indeed facilitate the process of neuroinflammation in DMD patients, besides the absence of dystrophin in brain tissue [15, 16]. Therefore, investigations on pathological mechanisms underlying skeletal muscle diseases followed by targeted clinical interventions are urgently needed.

In the last decades, important discoveries have emerged. This year Guglieri and colleagues published a study on JAMA after carrying out a randomized clinical trial that included 196 boys with DMD receiving 3 corticosteroid regimens (0.75 mg/kg of daily prednisone, 0.90 mg/kg of daily deflazacort, or 0.75 mg/kg of intermittent prednisone for 10 days on and then 10 days off). Remarkably, the results of this study demonstrated that daily prednisone or deflazacort resulted in significantly better outcomes compared with intermittent prednisone; there was no significant difference between the two daily regimens [17]. This finding represents an outstanding contribution to maximizing the use and beneficial outcomes of glucocorticoids not only in DMD but also in other myopathies. Previously existing data instead revealed that an intermittent regimen of oral prednisolone for two consecutive days per week in mdx mice resulted in an increased strength over time and improved survival between 80 and 104 weeks of age. Intermittent injection of prednisone or deflazacort at a minimal dose of once-weekly comparably benefitted sarcolemmal repair, fibrosis, and immune infiltrations as daily steroids in short-term experiments, while once-weekly versus daily prednisone induced opposite epigenetic and metabolic changes [18].

In an attempt to fight skeletal muscle diseases, several disease-modifying agents have been recently identified at the cellular level and are being investigated to offer the chance of a cure. For example, a growing number of studies show that dysregulation of autophagy and mitophagy aggravates muscle damage and contributes to disease progression in DMD. Accordingly, normalization of defective autophagy/mitophagy was suggested as a novel strategy to reduce muscle damage and promote muscle regeneration [19, 20]. Remarkably, Moore and colleagues demonstrated aberrant mitochondrial morphology, reduced number of mitochondrial cristae, and large mitochondrial vacuoles from both male and female mdx mice before the onset of muscle damage, thus reinforcing the evidence that these targets may yield novel therapeutic targets for the prevention and management of DMD [21]. It is also known that autophagy and inflammation exist in a complex relationship. Autophagy plays a critical role in the development, homeostasis, and survival of inflammatory cells, including macrophages, neutrophils, and lymphocytes, which play critical roles in the development and pathogenesis of inflammation. Inflammatory factors (e.g., NF-κB), are in turn critical regulator of autophagy in skeletal muscle [22].

Yet, fascinating studies revealed that fibroadipogenic progenitors (FAP) influence the regeneration potential of satellite cells during disease progression in mdx mice and mediate HDACi ability to selectively promote regeneration at the early stages of the disease [23, 24].

Again, in the last years, a lot has been learned about the association between gut microbiota with skeletal muscle homeostasis and function [25, 26]. However, the mechanisms through which intestinal microorganisms exert their influence on skeletal muscle remain largely undefined. To date, nothing is known about the potential implication of gut microbiota in skeletal muscle disorders. In this context, my research group has recently obtained evidence that fecal microbiota along with circulating levels of their metabolites is significantly altered between mdx and healthy mice. Therefore, we demonstrated that gut microbiota in dystrophic mice represent a novel disease-modifying agent to target for the development of new treatments.

In conclusion, this book topic is devoted to encompassing preclinical research and clinical studies on hereditary and acquired skeletal muscle disorders, ranging from molecular mechanisms to implications of clinical practice.