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Mounting evidence underscores the intricate interplay between the immune system and skeletal muscles in Duchenne muscular dystrophy (DMD), as well as during regular muscle regeneration. While immune cell infiltration into skeletal muscles stands out as a prominent feature in the disease pathophysiology, a myriad of secondary defects involving metabolic and inflammatory pathways persist, with the key players yet to be fully elucidated. Steroids, currently the sole effective therapy for delaying onset and symptom control, come with adverse side effects, limiting their widespread use. Preliminary evidence spotlighting the distinctive features of T cell profiling in DMD prompts the immuno-characterization of circulating cells. A molecular analysis of their transcriptome and secretome holds the promise of identifying a subpopulation of cells suitable as disease biomarkers. Furthermore, it provides a gateway to unraveling new pathological pathways and pinpointing potential therapeutic targets. Simultaneously, the last decade has witnessed the emergence of novel approaches. The development and equilibrium of both innate and adaptive immune systems are intricately linked to the gut microbiota. Modulating microbiota-derived metabolites could potentially exacerbate muscle damage through immune system activation. Concurrently, genome sequencing has conferred clinical utility for rare disease diagnosis since innovative methodologies have been deployed to interpret the functional consequences of genomic variations. Despite numerous genes falling short as clinical targets for MD, the exploration of Tdark genes holds promise for unearthing novel and uncharted therapeutic insights. In the quest to expedite the translation of fundamental knowledge into clinical applications, the identification of novel biomarkers and disease targets is paramount. This initiative not only advances our understanding but also paves the way for the design of innovative therapeutic strategies, contributing to enhanced care for individuals grappling with these incapacitating diseases.

In Duchenne muscular dystrophy (DMD), sarcolemma fragility and myofiber necrosis produce cellular debris that attract inflammatory cells. Macrophages and T-lymphocytes infiltrate muscles in response to damage-associated molecular pattern signalling and the release of TNF-α, TGF-β and interleukins prevent skeletal muscle improvement from the inflammation. This immunological scenario was extended by the discovery of a specific response to muscle antigens and a role for regulatory T cells (Tregs) in muscle regeneration. Normally, autoimmunity is avoided by autoreactive T-lymphocyte deletion within thymus, while in the periphery Tregs monitor effector T-cells escaping from central regulatory control. Here, we report impairment of thymus architecture of mdx mice together with decreased expression of ghrelin, autophagy dysfunction and AIRE down-regulation. Transplantation of dystrophic thymus in recipient nude mice determine the up-regulation of inflammatory/fibrotic markers, marked metabolic breakdown that leads to muscle atrophy and loss of force. These results indicate that involution of dystrophic thymus exacerbates muscular dystrophy by altering central immune tolerance. Immune cells are known to aggravate the inflammatory impact of Duchene muscular dystrophy. Here, the authors describe impaired thymic development and suggest thymic involution in this model of disease is linked to disease acceleration due to impaired immunological tolerance.

Growing evidence demonstrates the crosstalk between the immune system and the skeletal muscle in inflammatory muscle diseases and dystrophic conditions such as Duchenne Muscular Dystrophy (DMD), as well as during normal muscle regeneration. The rising of inflammation and the consequent activation of the immune system are hallmarks of DMD: several efforts identified the immune cells that invade skeletal muscle as CD4+ and CD8+ T cells, Tregs, macrophages, eosinophils and natural killer T cells. The severity of muscle injury and inflammation dictates the impairment of muscle regeneration and the successive replacement of myofibers with connective and adipose tissue. Since immune system activation was traditionally considered as a consequence of muscular wasting, we recently demonstrated a defect in central tolerance caused by thymus alteration and the presence of autoreactive T-lymphocytes in DMD. Although the study of innate and adaptive immune responses and their complex relationship in DMD attracted the interest of many researchers in the last years, the results are so far barely exhaustive and sometimes contradictory. In this review, we describe the most recent improvements in the knowledge of immune system involvement in DMD pathogenesis, leading to new opportunities from a clinical point-of-view.

Duchenne muscular dystrophy (DMD) arises from dystrophin deficiency, a crucial component of the dystrophin-glycoprotein complex (DGC) essential for maintaining cellular structural integrity by linking intracellular actin filaments to the basal lamina. Dysfunctions within this complex, coupled with increased inflammatory immune cell infiltration, contribute to the onset of dilated cardiomyopathy (DCM). This cardiac condition, characterized by necrosis and fibrosis, significantly impairs left ventricular function. Despite various treatment approaches, reliable effects on these pathogenic mechanisms remain elusive. RNA-binding proteins play pivotal roles in modulating pathways often dysregulated in cardiac pathology. Notably, HuR, which is upregulated in fibrotic cardiac regions and modulates innate immune system activation, emerges as a promising target. We investigated HuR expression in cardiac tissues of mdx murine model of DMD and assessed the impact of its inhibition with regards to DCM progression. Our findings reveal that HuR is indeed upregulated in mdx mice, and its inhibition leads to attenuation of cardiac fibrosis and improvement in heart function. These preclinical results underscore the potential of targeting HuR for therapeutic intervention to mitigate DCM-associated pathological changes, warranting further exploration for the development of effective treatments.

Muscular dystrophies and inflammatory myopathies are heterogeneous muscular disorders characterized by progressive muscle weakness and mass loss. Despite the high variability of etiology, inflammation and involvement of both innate and adaptive immune response are shared features. The best understood immune mechanisms involved in these pathologies include complement cascade activation, auto-antibodies directed against muscular proteins or de-novo expressed antigens in myofibers, MHC-I overexpression in myofibers, and lymphocytes-mediated cytotoxicity. Intravenous immunoglobulins (IVIGs) administration could represent a suitable immunomodulator with this respect. Here we focus on mechanisms of action of immunoglobulins in muscular dystrophies and inflammatory myopathies highlighting results of IVIGs from pre-clinical and case reports evidences.

Duchenne muscular dystrophy (DMD) is a progressive severe muscle‐wasting disease caused by mutations in DMD , encoding dystrophin, that leads to loss of muscle function with cardiac/respiratory failure and premature death. Since dystrophic muscles are sensed by infiltrating inflammatory cells and gut microbial communities can cause immune dysregulation and metabolic syndrome, we sought to investigate whether intestinal bacteria support the muscle immune response in mdx dystrophic murine model. We highlighted a strong correlation between DMD disease features and the relative abundance of Prevotella . Furthermore, the absence of gut microbes through the generation of mdx germ‐free animal model, as well as modulation of the microbial community structure by antibiotic treatment, influenced muscle immunity and fibrosis. Intestinal colonization of mdx mice with eubiotic microbiota was sufficient to reduce inflammation and improve muscle pathology and function. This work identifies a potential role for the gut microbiota in the pathogenesis of DMD. Synopsis The susceptibility of DMD patients to inflammatory events cannot solely be explained by skeletal muscle genetic defects but rather favors a new paradigm linking development of chronic inflammation with a strict regulation between epigenetics factors and degenerative environment. Gut microbiota–specific alterations (dysbiosis) correlate with the dystrophic pathology in mdx mice, influencing muscle immunity and fibrosis. Dysbiotic mdx microbiota induces a decreased innate immune response and altered muscle metabolism. The study of the dysregulated immune system‐microbiota axis in mdx mice highlights the importance of microbiota as a potential target for therapeutic interventions. Graphical Abstract The susceptibility of DMD patients to inflammatory events cannot solely be explained by skeletal muscle genetic defects but rather favors a new paradigm linking the development of chronic inflammation with a strict regulation between epigenetics factors and degenerative environment.

The insulin-like growth factor 2 receptor (IGF2R) plays a major role in binding and regulating the circulating and tissue levels of the mitogenic peptide insulin-like growth factor 2 (IGF2). IGF2/IGF2R interaction influences cell growth, survival, and migration in normal tissue development, and the deregulation of IGF2R expression has been associated with growth-related disease and cancer. IGF2R overexpression has been implicated in heart and muscle disease progression. Recent research findings suggest novel approaches to target IGF2R action. This review highlights recent advances in the understanding of the IGF2R structure and pathways related to muscle homeostasis.

Cells derived from blood vessels of human skeletal muscle can regenerate skeletal muscle, similarly to embryonic mesoangioblasts. However, adult cells do not express endothelial markers, but instead express markers of pericytes, such as NG2 proteoglycan and alkaline phosphatase (ALP), and can be prospectively isolated from freshly dissociated ALP + cells. Unlike canonical myogenic precursors (satellite cells), pericyte-derived cells express myogenic markers only in differentiated myotubes, which they form spontaneously with high efficiency. When transplanted into severe combined immune deficient–X-linked, mouse muscular dystrophy ( scid–mdx ) mice, pericyte-derived cells colonize host muscle and generate numerous fibres expressing human dystrophin. Similar cells isolated from Duchenne patients, and engineered to express human mini-dystrophin, also give rise to many dystrophin-positive fibres in vivo . These data show that myogenic precursors, distinct from satellite cells, are associated with microvascular walls in the human skeletal muscle, may represent a correlate of embryonic 'mesoangioblasts' present after birth and may be a promising candidate for future cell-therapy protocols in patients.

Extraordinary progress in understanding several key features of stem cells has been made in the last ten years, including definition of the niche, and identification of signals regulating mobilization and homing as well as partial understanding of the mechanisms controlling self-renewal, commitment, and differentiation. This progress produced invaluable tools for the development of rational cell therapy protocols that have yielded positive results in preclinical models of genetic and acquired diseases and, in several cases, have entered clinical experimentation with positive outcome. Adult mesenchymal stem cells (MSCs) are nonhematopoietic cells with multilineage potential to differentiate into various tissues of mesodermal origin. They can be isolated from bone marrow and other tissues and have the capacity to extensively proliferate in vitro. Moreover, MSCs have also been shown to produce anti-inflammatory molecules which can modulate humoral and cellular immune responses. Considering their regenerative potential and immunoregulatory effect, MSC therapy is a promising tool in the treatment of degenerative, inflammatory, and autoimmune diseases. It is obvious that much work remains to be done to increase our knowledge of the mechanisms regulating development, homeostasis, and tissue repair and thus to provide new tools to implement the efficacy of cell therapy trials.