The Transcription Factor Nfix Requires RhoA-ROCK1 Dependent Phagocytosis to Mediate Macrophage Skewing during Skeletal Muscle Regeneration

Macrophages (MPs) are immune cells which are crucial for tissue repair. In skeletal muscle regeneration, pro-inflammatory cells first infiltrate to promote myogenic cell proliferation, then they switch into an anti-inflammatory phenotype to sustain myogenic cells differentiation and myofiber formation. This phenotypical switch is induced by dead cell phagocytosis. We previously demonstrated that the transcription factor Nfix, a member of the nuclear factor I (Nfi) family, plays a pivotal role during muscle development, regeneration and in the progression of muscular dystrophies. Here, we show that Nfix is mainly expressed by anti-inflammatory macrophages. Upon acute injury, mice deleted for Nfix in myeloid line displayed a significant defect in the process of muscle regeneration. Indeed, Nfix is involved in the macrophage phenotypical switch and macrophages lacking Nfix failed to adopt an anti-inflammatory phenotype and interact with myogenic cells. Moreover, we demonstrated that phagocytosis induced by the inhibition of the RhoA-ROCK1 pathway leads to Nfix expression and, consequently, to acquisition of the anti-inflammatory phenotype. Our study identified Nfix as a link between RhoA-ROCK1-dependent phagocytosis and the MP phenotypical switch, thus establishing a new role for Nfix in macrophage biology for the resolution of inflammation and tissue repair

Silencing Nfix rescues muscular dystrophy by delaying muscle regeneration

Muscular dystrophies are severe disorders due to mutations in structural genes, and are characterized by skeletal muscle wasting, compromised patient mobility, and respiratory functions. Although previous works suggested enhancing regeneration and muscle mass as therapeutic strategies, these led to no long-term benefits in humans. Mice lacking the transcription factor Nfix have delayed regeneration and a shift toward an oxidative fiber type. Here, we show that ablating or silencing the transcription factor Nfix ameliorates pathology in several forms of muscular dystrophy. Silencing Nfix in postnatal dystrophic mice, when the first signs of the disease already occurred, rescues the pathology and, conversely, Nfix overexpression in dystrophic muscles increases regeneration and markedly exacerbates the pathology. We therefore offer a proof of principle for a novel therapeutic approach for muscular dystrophies based on delaying muscle regeneration

Ritual Design Toolkit

Rituals are intentional behaviours with a distinct emotional outcome. They fill our lives with deeper meaning and are found everywhere from the workplace to the kitchen table. We have made the Ritual Design Toolkit to help you understand rituals, how to harness them, and how to design them. In our own work, we have used the toolkit in a range of applications including enhancing key moments in a customer journey, helping people adopt healthier eating habits and building and strengthening communities. The toolkit can be used for grand rituals and micro-interactions. Whether you are a manager of a team, a packaging designer, or a service enthusiast, you can find guidance here to build more meaningful moments into your work. The toolkit offers a ritual design process consisting of three main steps: scoping, creating and testing rituals

Nutritional intervention with cyanidin hinders the progression of muscular dystrophy

Muscular Dystrophies are severe genetic diseases due to mutations in structural genes, characterized by progressive muscle wasting that compromises patients' mobility and respiratory functions. Literature underlined oxidative stress and inflammation as key drivers of these pathologies. Interestingly among different myofiber classes, type I fibers display a milder dystrophic phenotype showing increased oxidative metabolism. This work shows the benefits of a cyanidin-enriched diet, that promotes muscle fiber-type switch and reduced inflammation in dystrophic alpha-sarcoglyan (Sgca) null mice having, as a net outcome, morphological and functional rescue. Notably, this benefit is achieved also when the diet is administered in dystrophic animals when the signs of the disease are seriously evident. Our work provides compelling evidence that a cyanidin-rich diet strongly delays the progression of muscular dystrophies, paving the way for a combinatorial approach where nutritional-based reduction of muscle inflammation and oxidative stress facilitate the successful perspectives of definitive treatments

Evolution of scent genes in roses

International audienceKnowledge of the flowering process — an important trait in ornamental plants such as roses — is necessary for efficient control of flowering. This study was carried out to develop and characterize new resources to gain further insight into floral control in rose. We studied floral initiation in a nonrecurrent blooming rose (hybrid of Rosa wichurana ) and a recurrent blooming rose ( Rosa hybrida Black Baccara ® ). In Black Baccara ® , floral initiation took place rapidly after bud burst, whereas in the greenhouse R. wichurana remained vegetative. During floral initiation, the apex enlarged and domed quickly and concomitantly. This is the first description of this transition between the vegetative and floral bud stages in rose. From these vegetative and pre-floral tissues, two cDNA libraries were constructed and 5000 ESTs sequenced. By collecting our ESTs and those available in public databases, we developed a comprehensive database representing ~5000 unique sequences after clustering. By screening this database for candidate genes involved in the flowering process, we identified 13 genes potentially involved in gibberellic acid signalling, photoperiod pathways, and floral development. Based on expression data, we put forward different hypotheses on the control of flowering in rose (photoperiod control and involvement of gibberellins) relative to what is already known in Arabidopsis

Rebalancing expression of HMGB1 redox isoforms to counteract muscular dystrophy

Muscular dystrophies (MDs) are a group of genetic diseases characterized by progressive muscle wasting associated to oxidative stress and persistent inflammation. It is essential to deepen our knowledge on the mechanism connecting these two processes because current treatments for MDs have limited efficacy and/or are associated with side effects. Here, we identified the alarmin high-mobility group box 1 (HMGB1) as a functional link between oxidative stress and inflammation in MDs. The oxidation of HMGB1 cysteines switches its extracellular activities from the orchestration of tissue regeneration to the exacerbation of inflammation. Extracellular HMGB1 is present at high amount and undergoes oxidation in patients with MDs and in mouse models of Duchenne muscular dystrophy (DMD) and limb-girdle muscular dystrophy 3 (LGMDR3) compared to controls. Genetic ablation of HMGB1 in muscles of DMD mice leads to an amelioration of the dystrophic phenotype as evidenced by the reduced inflammation and muscle degeneration, indicating that HMGB1 oxidation is a detrimental process in MDs. Pharmacological treatment with an engineered nonoxidizable variant of HMGB1, called 3S, improves functional performance, muscle regeneration, and satellite cell engraftment in dystrophic mice while reducing inflammation and fibrosis. Overall, our data demonstrate that the balance between HMGB1 redox isoforms dictates whether skeletal muscle is in an inflamed or regenerating state, and that the nonoxidizable form of HMGB1 is a possible therapeutic approach to counteract the progression of the dystrophic phenotype. Rebalancing the HMGB1 redox isoforms may also be a therapeutic strategy for other disorders characterized by chronic oxidative stress and inflammation