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Role of the transcription factor Nfix in muscle regeneration and muscular dystrophies

Final Report Summary - REGENERATIONFIX (Role of the transcription factor Nfix in muscle regeneration and muscular dystrophies)

Skeletal muscle is the tissue responsible for posture, locomotion and diaphragmatic breathing. The molecular mechanisms regulating muscle differentiation and maturation are quite well characterized. Interestingly, skeletal myogenesis occurs in successive, distinct though overlapping developmental stages that involve different cell populations and expression of different genes. Skeletal muscle is, in fact, a heterogeneous tissue composed of individual muscle fibres, diversified in size, shape and contractile protein content, to fulfill the different functional needs of the vertebrate body. This heterogeneity derives and depends, at least in part, upon distinct classes of myogenic progenitors, i.e. embryonic, fetal and adult myoblasts (satellite cells). In our previous study, we demonstrated the role of the transcription factor Nuclear Factor IX, Nfix, in driving the transcriptional switch from embryonic to fetal myogenesis, characterized by a switch from slow to fast twitching and more mature fibres. Preliminary data in our lab showed that Nfix was also strongly expressed in satellite cells (SCs), the muscle adult stem cells responsible for post-natal muscle growth and regeneration. SCs are present in healthy adult mammalian muscle as quiescent cells and represent 2.5%–6% of all nuclei of a given muscle fiber. However, when activated by muscle injury, they can generate large numbers of new myofibres within just a few days. The comprehension of the proper biology of SCs is extremely important for applicative studies on the Muscular Dystrophies (MDs) such as the Duchenne Muscular Dystrophy. MDs are clinically and molecularly heterogeneous diseases, characterized by primary wasting of skeletal muscle that compromise patient mobility and, in the most severe case, respiratory and cardiac functions, leading to wheelchair dependency, respiratory failure and premature death. In many cases, the mutation affects proteins that form a link between the cytoskeleton and the basal lamina. Absence of one protein often causes the disassembly of the whole multiprotein complex associated with dystrophin, leading to increased fragility of the sarcolemma, especially during intense contractile activity. Damaged or dead fibers can be repaired or replaced by SCs. However, dystrophic satellite cells share the same molecular defect and produce fibers that are also prone to degeneration. With time, the population of satellite cells is exhausted and the muscle tissue is progressively replaced by connective and adipose tissue. Among the different therapies proposed for the MDs, many efforts are directed to make dystrophic muscles hypertrophic and thus stronger to counteract the progressive degeneration. This is obtained at the expense of satellite cell proliferation and differentiation, whose pool is large in mice but limited in humans. Our data revealed that Nfix is also strongly expressed in SCs. Therefore, our project aimed to know if and how Nfix may play a role in post-natal muscle growth, regeneration and whether Nfix function can be important in the pathogenesis of MDs.
We obtained important results, which demonstrated that Nfix is essential in driving the proper timing of muscle regeneration upon muscle damage through satellite cell-specific mechanisms and involves the expression of a muscle growth inhibitor called Myostatin. Notably, we also demonstrated that in a dystrophic context, the absence of Nfix leads to a morphological and functional amelioration of the dystrophic histopathology over time as a consequence of a general switch towards a slow-twitching contraction and a reduced muscle regeneration which better protect muscle wasting in time.
The results of this study will have important implications for the understanding of the mechanisms regulating post-natal muscle growth and regeneration and potentially lead to a novel therapy for muscular dystrophy.