Abstract
The muscle stem cells niche is essential in neuromuscular disorders. Muscle injury and myofiber death are the main triggers of muscle regeneration via satellite cell activation. However, in degenerative diseases such as muscular dystrophy, regeneration still keep elusive. In these pathologies, stem cell loss occurs over time, and missing signals limiting damaged tissue from activating the regenerative process can be envisaged. It is unclear what comes first: the lack of regeneration due to satellite cell defects, their pool exhaustion for degeneration/regeneration cycles, or the inhibitory mechanisms caused by muscle damage and fibrosis mediators. Herein, Duchenne muscular dystrophy has been taken as a paradigm, as several drugs have been tested at the preclinical and clinical levels, targeting secondary events in the complex pathogenesis derived from lack of dystrophin. We focused on the crucial roles that pro-inflammatory and pro-fibrotic cytokines play in triggering muscle necrosis after damage and stimulating satellite cell activation and self-renewal, along with growth and mechanical factors. These processes contribute to regeneration and niche maintenance. We review the main effects of drugs on regeneration biomarkers to assess whether targeting pathogenic events can help to protect niche homeostasis and enhance regeneration efficiency other than protecting newly formed fibers from further damage.
Highlights
The muscle stem cells niche is essential in neuromuscular disorders
Considering the great amount of preclinical data available on the mdx mouse model and the plethora of new compounds proposed and repurposed as potentially effective treatments in Duchenne muscular dystrophy (DMD), specific attention has been devoted to describing the impacts of drugs targeting muscle stem cell niche homeostasis in the regenerative process, of those directed against pro-inflammatory and pro-fibrotic mediators, and of drugs directly aimed at directly modulating satellite cell self-renewal
DMD is a prototype of the efforts in this field, due to the intense research aimed at identifying potential therapies
Summary
Skeletal muscle is a complex and heterogeneous tissue with a high regeneration potential and plasticity. Most of the progeny fuse with the adjacent fibers, with new nuclei contributing to growing muscle fibers (whose nuclei are not able to divide) Because of this process, it is possible to think that the majority of the nuclei of a mature muscle are probably derived from satellite cells. When postnatal growth is finished, satellite cells enter a phase of quiescence, but they can be activated when the muscle tissue is damaged or in response to further growth demands. In these cases, satellite cells exit the quiescent state, and undergo a number of cells divisions, thereby producing fusion competent cells that are able either to fuse with damaged fibers or to form new ones. A very important one, for example, is represented by nutrient administration in the maternal stage, which seems to have a direct role in perinatal muscle growth, as extensively explained in Fiorotto and Davis [12]
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