Role of thrombospondin 1 in macrophage inflammation in dysferlin myopathy

Muscle inflammation can be a prominent feature in several muscular dystrophies. In dysferlin myopathy, it is mainly composed of macrophages. To understand the origin of inflammation in dysferlin-deficient muscle, we analyzed soluble factors involved in monocyte chemotaxis released by myoblasts and myotubes from control and dysferlinopathy patients using a transwell system. Dysferlin-deficient myotubes released more soluble factors involved in monocyte chemotaxis compared with controls (p < 0.001). Messenger RNA microarray analysis showed a 3.2-fold increase of thrombospondin 1 (TSP-1) expression in dysferlin-deficient myotubes. Retrotranscriptasepolymerase chain reaction analysis, ELISA, and immunohistochemistry confirmed these results. Dysferlin mRNA knockdown with short-interfering RNA in normal myogenic cells resulted in TSP-1 mRNA upregulation and increased chemotaxis. Furthermore, monocyte chemotaxis was decreased when TSP-1 was blocked by specific antibodies. In muscle biopsies from dysferlinopathy patients, TSP-1 expression was increased in muscle fibers but not in biopsies of patientswith other myopathies with inflammation; TSP-1 was seen in some macrophages in all samples analyzed. Taken together, the data demonstrate that dysferlin-deficient muscle upregulates TSP-1 in vivoand in vitro and indicate that endogenous chemotactic factors arecrucial to the sustained inflammatory process observed in dysferlinopathies. © 2010 by the American Association of Neuropathologists, Inc.This work was supported by the Beca del Fondo de Investigacion Sanitaria PI06/0455 and by the Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas.Peer Reviewe

Differentially activated macrophages orchestrate myogenic precursor cell fate during human skeletal muscle regeneration.

Marielle Saclier and Houda Yacoub-Youssef : Both should be considered as first authorInternational audienceMacrophages (MPs) exert either beneficial or deleterious effects on tissue repair, depending on their activation/polarization state. They are crucial for adult skeletal muscle repair, notably by acting on myogenic precursor cells. However, these interactions have not been fully characterized. Here, we explored both in vitro and in vivo, in human, the interactions of differentially activated MPs with myogenic precursor cells (MPCs) during adult myogenesis and skeletal muscle regeneration. We showed in vitro that through the differential secretion of cytokines and growth factors, proinflammatory MPs inhibited MPC fusion while anti-inflammatory MPs strongly promoted MPC differentiation by increasing their commitment into differentiated myocytes and the formation of mature myotubes. Furthermore, the in vivo time course of expression of myogenic and MP markers was studied in regenerating human healthy muscle after damage. We observed that regenerating areas containing proliferating MPCs were preferentially associated with MPs expressing proinflammatory markers. In the same muscle, regenerating areas containing differentiating myogenin-positive MPCs were preferentially coupled to MPs harboring anti-inflammatory markers. These data demonstrate for the first time in human that MPs sequentially orchestrate adult myogenesis during regeneration of damaged skeletal muscle. These results support the emerging concept that inflammation, through MP activation, controls stem cell fate and coordinates tissue repair

Aging Disrupts Muscle Stem Cell Function by Impairing Matricellular WISP1 Secretion from Fibro-Adipogenic Progenitors

Research on age-related regenerative failure of skeletal muscle has extensively focused on the phenotypes of muscle stem cells (MuSCs). In contrast, the impact of aging on regulatory cells in the MuSC niche remains largely unexplored. Here, we demonstrate that aging impairs the function of mouse fibro- adipogenic progenitors (FAPs) and thereby indirectly affects the myogenic potential of MuSCs. Using transcriptomic profiling, we identify WNT1 Inducible Signaling Pathway Protein 1 (WISP1) as a FAP-derived matricellular signal that is lost during aging. WISP1 is required for efficient muscle regeneration and controls the expansion and asymmetric commitment of MuSCs through Akt signaling. Transplantation of young FAPs or systemic treatment with WISP1 restores the myogenic capacity of MuSCs in aged mice and rescues skeletal muscle regeneration. Our work establishes that loss of WISP1 from FAPs contributes to MuSC dysfunction in aged skeletal muscles and demonstrates that this mechanism can be targeted to rejuvenate myogenesis