Skeletal muscle is a highly adaptive tissue, with remarkable potential to regenerate and recover in response to injury and environmental demands. Pathological conditions, from inherited defects to chronic illnesses, can compromise homeostasis, resulting in loss of muscle mass, functional impairment, and altered systemic metabolism. With over 1042 conditions and 587 associated genes, neuromuscular diseases as a group (i.e. diseases primarily affecting skeletal muscle or lower motor neuron and skeletal muscle) account for an estimated prevalence at least similar to that of Parkinson’s disease and twice that of multiple sclerosis worldwide.
Testing of new therapeutic strategies, from antisense oligonucleotides to stem cell and enzyme replacement therapies, have put these diseases at the forefront of therapy development for human conditions. Of note, increasing evidence in preclinical models and in clinical trials suggest that preserving muscle function may result in systemic anti-aging effects, potentially further expanding these applications outside of muscle diseases sensu stricto.
While skeletal muscle offers substantial opportunities compared to other tissues (e.g. several monogenic diseases, easy accessibility for sampling and assessment), there are unique challenges which are becoming apparent as these approaches move into clinical applications. For example in the context of treatment options for Duchenne muscular dystrophy (DMD), there has been considerable success in using truncated dystrophin or ‘minidystrophin’, to accommodate the limited cloning capacity of the viral vector. Nevertheless, a substantial financial and technical limitation to the clinical translation is the production of sufficient amounts of virus to guarantee widespread distribution to all muscle tissues, which account for 40-45% of body weight. Other potential hurdles are the immunological risks associated with high dose administration, particularly to an immature immune system, given that DMD, as many other genetic muscular conditions, affect the paediatric population. Muscle also offers unique opportunities for development of cell-based therapies to promote skeletal muscle regeneration following injury and disease. Many stem cell populations are implicated in muscle regeneration, including but not limited to satellite cells, mesenchymal stem cells, adipose-derived stem cells, hematopoietic stem cells, pericytes, and fibroadipogenic progenitors. However, clinical testing has exposed challenges associated with the isolation, delivery, and survival of these cells.
Overall, the unexpected challenges posed by muscle (e.g. complex cell heterogeneity, high functional specialization, tissue abundance), require a deeper understanding of the fundamental mechanisms governing the maintenance of muscle mass in health and disease. This knowledge, together with advancements in the development and therapeutic implementation of gene therapy strategies which are already on the horizon, are expected to revolutionize in the near future the clinical management of patients with muscle diseases and beyond.
The aim of this Research Topic is to bring together international experts in the areas of muscle physiology, neuromuscular research, translational research, gene and cell therapy in the context of neuromuscular diseases to provide a deep overview and analysis of scientifically sound evidence that highlights the challenges and opportunities of targeting muscle for therapy. All types of articles reporting basic, translational, experimental, or clinical research are welcome.
Skeletal muscle is a highly adaptive tissue, with remarkable potential to regenerate and recover in response to injury and environmental demands. Pathological conditions, from inherited defects to chronic illnesses, can compromise homeostasis, resulting in loss of muscle mass, functional impairment, and altered systemic metabolism. With over 1042 conditions and 587 associated genes, neuromuscular diseases as a group (i.e. diseases primarily affecting skeletal muscle or lower motor neuron and skeletal muscle) account for an estimated prevalence at least similar to that of Parkinson’s disease and twice that of multiple sclerosis worldwide.
Testing of new therapeutic strategies, from antisense oligonucleotides to stem cell and enzyme replacement therapies, have put these diseases at the forefront of therapy development for human conditions. Of note, increasing evidence in preclinical models and in clinical trials suggest that preserving muscle function may result in systemic anti-aging effects, potentially further expanding these applications outside of muscle diseases sensu stricto.
While skeletal muscle offers substantial opportunities compared to other tissues (e.g. several monogenic diseases, easy accessibility for sampling and assessment), there are unique challenges which are becoming apparent as these approaches move into clinical applications. For example in the context of treatment options for Duchenne muscular dystrophy (DMD), there has been considerable success in using truncated dystrophin or ‘minidystrophin’, to accommodate the limited cloning capacity of the viral vector. Nevertheless, a substantial financial and technical limitation to the clinical translation is the production of sufficient amounts of virus to guarantee widespread distribution to all muscle tissues, which account for 40-45% of body weight. Other potential hurdles are the immunological risks associated with high dose administration, particularly to an immature immune system, given that DMD, as many other genetic muscular conditions, affect the paediatric population. Muscle also offers unique opportunities for development of cell-based therapies to promote skeletal muscle regeneration following injury and disease. Many stem cell populations are implicated in muscle regeneration, including but not limited to satellite cells, mesenchymal stem cells, adipose-derived stem cells, hematopoietic stem cells, pericytes, and fibroadipogenic progenitors. However, clinical testing has exposed challenges associated with the isolation, delivery, and survival of these cells.
Overall, the unexpected challenges posed by muscle (e.g. complex cell heterogeneity, high functional specialization, tissue abundance), require a deeper understanding of the fundamental mechanisms governing the maintenance of muscle mass in health and disease. This knowledge, together with advancements in the development and therapeutic implementation of gene therapy strategies which are already on the horizon, are expected to revolutionize in the near future the clinical management of patients with muscle diseases and beyond.
The aim of this Research Topic is to bring together international experts in the areas of muscle physiology, neuromuscular research, translational research, gene and cell therapy in the context of neuromuscular diseases to provide a deep overview and analysis of scientifically sound evidence that highlights the challenges and opportunities of targeting muscle for therapy. All types of articles reporting basic, translational, experimental, or clinical research are welcome.
