Understanding the circuits that promote an efficient resolution of inflammation is crucial to deciphering the molecular and cellular processes required to promote tissue repair. Macrophages play a central role in the regulation of inflammation, resolution, and repair/regeneration. Using a model of skeletal muscle injury and repair, herein we identified annexin A1 (AnxA1) as the extracellular trigger of macrophage skewing toward a pro-reparative phenotype. Brought into the injured tissue initially by migrated neutrophils, and then overexpressed in infiltrating macrophages, AnxA1 activated FPR2/ALX receptors and the downstream AMPK signaling cascade, leading to macrophage skewing, dampening of inflammation, and regeneration of muscle fibers. Mice lacking AnxA1 in all cells or only in myeloid cells displayed a defect in this reparative process. In vitro experiments recapitulated these properties, with AMPK-null macrophages lacking AnxA1-mediated polarization. Collectively, these data identified the AnxA1/FPR2/AMPK axis as an important pathway in skeletal muscle injury regeneration.

Skeletal muscle shows high plasticity in response to external demand. Moreover, adult skeletal muscle is capable of complete regeneration after injury, due to the properties of muscle stem cells (MuSCs), the satellite cells, which follow a tightly regulated myogenic program to generate both new myofibers and new MuSCs for further needs. Although reactive oxygen species (ROS) and reactive nitrogen species (RNS) have long been associated with skeletal muscle physiology, their implication in the cell and molecular processes at work during muscle regeneration is more recent. This review focuses on redox regulation during skeletal muscle regeneration. An overview of the basics of ROS/RNS and antioxidant chemistry and biology occurring in skeletal muscle is first provided. Then, the comprehensive knowledge on redox regulation of MuSCs and their surrounding cell partners (macrophages, endothelial cells) during skeletal muscle regeneration is presented in normal muscle and in specific physiological (exercise-induced muscle damage, aging) and pathological (muscular dystrophies) contexts. Recent advances in the comprehension of these processes has led to the development of therapeutic assays using antioxidant supplementation, which result in inconsistent efficiency, underlying the need for new tools that are aimed at precisely deciphering and targeting ROS networks. This review should provide an overall insight of the redox regulation of skeletal muscle regeneration while highlighting the limits of the use of nonspecific antioxidants to improve muscle function. Antioxid. Redox Signal. 27, 276–310.

The discovery of new non-canonical (i.e. non-innate immune) functions of macrophages has been a recurring theme over the past 20 years. Indeed, it has emerged that macrophages can influence the development, homeostasis, maintenance and regeneration of many tissues and organs, including skeletal muscle, cardiac muscle, the brain and the liver, in part by acting directly on tissue-resident stem cells. In addition, macrophages play crucial roles in diseases such as obesity-associated diabetes or cancers. Increased knowledge of their regulatory roles within each tissue will therefore help us to better understand the full extent of their functions and could highlight new mechanisms modulating disease pathogenesis. In this Review, we discuss recent studies that have elucidated the developmental origins of various macrophage populations and summarize our knowledge of the non-canonical functions of macrophages in development, regeneration and tissue repair.

Background and objective: The idiopathic inflammatory myopathy Dermatomyositis (DM) is an acquired disease that combines muscle, lung and skin impairments. DM patients show a wide range of severity of proximal skeletal muscle weakness, associated with inflammatory infiltrates, vasculitis, and capillary dropout, perifascicular myofiber atrophy. Moreover, DM muscles show signs of muscle regeneration. Since muscle stem cells (MuSCs) are responsible for myofiber repair, we asked wether the proliferative properties of muscle stem cells (MuSCs) are altered in DM muscle. We investigated the role of type-I interferon (IFN-I) in this process since DM is associated with sustained inflammation with high IFN-I levels. Methods: MuSCs isolated from normal, adult and juvenile DM muscles were grown in culture and were analyzed in vitro for their proliferating properties, their myogenic capacities and their senescence. Gain and loss of function experiments were performed to assess the role of IFN-I signaling in the prolfierative capacities of MuSCs. Results: MuSCs derived from 8 DM adult patients (DM-MuSCs) (5 severe form and 3 mild form, established from histological evaluation), from 3 juvenile DM patients and from normal muscle were used to analyze their myogenesis in vitro. DM-MuSCs exhibited strongly reduced proliferating capacities as compared with healthy MuSCs (-31 to -43% for severe and mild DM, respectively), leading to poor myotube formation (-36 to -71%). DM-MuSCs were enriched in senescent, beta-galactosidase positive cells, explaining partly the proliferation defect. Gain and loss of function experiments were performed to assess the role of IFN-I on the proliferative capacity of MuSCs. High concentrations of IFN-I decreased the proliferation of healthy MuSCs. Similarly, conditioned-medium from DM-MuSCs decreased the proliferation of healthy MuSC (-15 to -22%), suggesting the delivery of an autocrine effector. Then, pharmacological blockade of the IFN signaling (using ruxolitinib or anti-IFN-receptor antibodies) in DM-MuSCs rescued their proliferation up to the control values. Discussion: These results show that autocrine IFN-I signaling prevents MuSC expansion, leading to muscle repair deficit. This process may explain the persistent muscle weakness observed in severe DM patients.