Cellular Cross-talk in Neuromuscular Diseases and Targets for Therapeutic Intervention

Neuromuscular diseases comprise a heterogeneous group of disorders characterized by progressive impairment of muscle function resulting from defects in muscle fibers, motor neurons, or their interactions. Beyond cell-autonomous defects, growing evidence indicates that disrupted cellular cross-talk among myocytes, fibroblasts, immune cells, and neurons plays a central role in disease initiation and progression. Alterations in these intercellular communication networks contribute to muscle degeneration, chronic inflammation, fibrosis, and neuromuscular dysfunction, ultimately leading to loss of mobility and systemic complications.Muscle degeneration in neuromuscular diseases is frequently accompanied by sustained inflammatory responses and excessive extracellular matrix deposition by activated fibroblasts, resulting in fibrotic tissue that replaces functional muscle. These pathological changes profoundly alter the muscle microenvironment and interfere with muscle regeneration and neuromuscular signaling. In parallel, increasing evidence points to the involvement of the nervous system, with cognitive, autonomic and motor control abnormalities reported in several neuromuscular conditions, highlighting the need to understand muscle–nerve–stromal interactions at a systems level.Current therapeutic strategies for neuromuscular diseases primarily aim to correct or compensate for the underlying genetic or molecular defects, including gene replacement, gene editing, RNA-based therapies, and pharmacological modulation. While these approaches have shown promising results, major challenges remain, such as efficient tissue targeting, long-term efficacy, immune responses, and incomplete knowledge of how these therapies affect non-muscle cell populations and intercellular communication pathways. Targeting cellular cross-talk and the pathological interactions between different cell types may therefore represent a powerful complementary therapeutic strategy.Fibroblasts have emerged as key regulators of the muscle microenvironment in neuromuscular diseases, yet their role remains underexplored compared to that of myocytes and neurons. Aberrant fibroblast activation, altered metabolic states, and dysfunctional signaling with muscle and nerve cells contribute to fibrosis, impaired regeneration, and neuromuscular junction instability. Understanding the molecular and functional interactions between fibroblasts, myocytes, immune cells, and neurons is essential for identifying novel biomarkers and therapeutic targets.This Research Topic aims to explore the mechanisms of cellular-cross talk in neuromuscular diseases and to identify targets for therapeutic intervention. By integrating studies on muscle, stromal, immune and neural cell populations, this topic seeks to provide a comprehensive view of how intercellular communication drives disease progression and influences treatment outcomes. Particular emphasis will be placed on fibroblast plasticity, extracellular matrix remodeling, neuromuscular connectivity, and the impact of pathological signaling on motor control and nervous system function.Furthermore, this Research Topic encourages the development and evaluation of therapeutic approaches that modulate cellular interactions, including anti-fibrotic, anti-inflammatory, metabolic, and neuroprotective strategies, alone or in combination with gene-based therapies. Understanding how these interventions reshape intercellular signaling networks may enable the design of more effective, combinatorial treatments applicable across multiple neuromuscular disorders.We welcome original research articles, reviews, and perspectives addressing, but not limited to, the following topics:• Cellular cross-talk among myocytes, fibroblasts, immune cells, and neurons in neuromuscular diseases.• Role of fibroblasts in muscle degeneration, regeneration, and fibrosis.• Fibroblast–myocyte and fibroblast–neuron signaling pathways.• Altered fibroblast metabolism and mitochondrial function in neuromuscular disorders.• Proteomic and secretomic profiling of fibroblasts and muscle cells.• Molecular mechanisms linking inflammation, fibrosis, and neuromuscular dysfunction.• Neurological and neuromuscular junction alterations driven by disrupted cellular communication.• Identification of biomarkers reflecting pathological intercellular signaling.• Therapeutic molecules targeting fibrosis and maladaptive cellular interactions.• Synergistic effects of gene-based therapies with anti-fibrotic or anti-inflammatory approaches.• Impact of emerging therapies on neuromuscular connectivity and nervous system function. Topic editors: Sandrine Herbelet, Laila A. Damiati, Marwa El Soury Source: https://www.frontiersin.org/research-topics/78368/cellular-cross-talk-in-neuromuscular-diseases-and-targets-for-therapeutic-intervention