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Costamagna, D.

Publications and source records attributed to Costamagna, D..

3 recordsLinked to original sources

Adult stem cell characterization from the Medial Gastrocnemius and Semitendinosus muscles in early development of cerebral palsy pathology

Cerebral palsy (CP) is one of the most common lifelong conditions leading to childhood physical disability. Literature reported previously altered muscle properties such as lower number of satellite cells (SCs), with altered fusion capacity. However, these observations highly vary among studies, possibly due to heterogeneity in patient population, lack of appropriate control data, methodology and different assessed muscle. In this study we aimed to strengthen previous observations and to understand the heterogeneity of CP muscle pathology. Myogenic differentiation of SCs from the Medial Gastrocnemius (MG) muscle of patients with CP (n=16, 3-9 years old) showed higher fusion capacity compared to age-matched typically developing children (TD, n=13). Furthermore, we uniquely assessed cells of two different lower limb muscles and showed a decreased myogenic potency in cells from the Semitendinosus (ST) compared to the MG. Longitudinal assessments, one year after the first botulinum toxin treatment, showed slightly reduced SC representations and lower fusion capacity. Finally, we proved the robustness of our data, by assessing in parallel the myogenic capacity of two samples from the same TD muscle. In conclusion, these data confirmed previous findings of increased SC fusion capacity from MG muscle of young patients with CP compared to age-matched TD. Further elaboration is reported on potential factors contributing to heterogeneity, such as assessed muscle, CP progression and reliability of primary outcome parameters.

developmental biology↗

PGC-1α in the myofibers regulates the balance between myogenic and adipogenic progenitors affecting muscle regeneration

Skeletal muscle repair is accomplished by satellite cells (MuSC) in cooperation with interstitial stromal cells (ISCs). So far, the relationship between the function of these cells and the metabolic state of myofibers remains unclear. The present study reports alterations in the proportion of both MuSCs and adipogenesis regulators (Aregs) induced by overexpression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1) in the myofibers (MCK-PGC-1 mice). Although PGC-1-driven increase of MuSCs does not accelerate muscle regeneration, myogenic progenitors isolated from MCK-PGC-1 mice and transplanted into intact and regenerating muscles are more prone to fuse with recipient myofibers than those derived from WT donors. Moreover, both young and aged MCK-PGC-1 animals show reduced perilipin-positive areas when challenged with an adipogenic stimulus, demonstrating low propensity to accumulate adipocytes within the muscle. These results provide new insights on the role played by PGC-1 in promoting myogenesis and hindering adipogenesis in the skeletal muscle.

molecular biology↗

Human iPSC-Based Model Reveals NOX4 as Therapeutic Target in Duchenne Cardiomyopathy

Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle disorder, caused by mutations in the Dystrophin gene. Cardiomyopathy is one of the major causes of early death. In this study, we used DMD patient-specific induced pluripotent stem cells (iPSCs) to model cardiomyopathic features in DMD and unravel novel pathological mechanistic insights. Cardiomyocytes (CMs) differentiated from DMD iPSCs showed enhanced premature cell death, due to significantly elevated intracellular reactive oxygen species (ROS) concentrations, as a result of depolarized mitochondria and high NADPH oxidase 4 (NOX4) protein levels. Genetic correction of Dystrophin through CRISPR/Cas9 editing restored normal ROS levels. Application of ROS reduction by N-acetyl-L-cysteine (NAC), partial Dystrophin re-expression by ataluren (PTC124) and enhancing mitochondrial electron transport chain function by idebenone improved cell survival of DMD iPSC-CMs. We show applications that could counteract the detrimental oxidative stress environment in DMD iPSC-CMs by stimulating adenosine triphosphate (ATP) production. ATP could bind to the ATP-binding domain in the NOX4 enzyme, and we demonstrate that ATP resulted in partial inhibition of the NADPH-dependent ROS production of NOX4. Considering the complexity and the early cellular stress responses in DMD cardiomyopathy, we propose to target ROS production and prevent the detrimental effects of NOX4 on DMD CMs as a promising therapeutic strategy. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC="FIGDIR/small/460090v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@d3606borg.highwire.dtl.DTLVardef@15f1d88org.highwire.dtl.DTLVardef@18bfb9corg.highwire.dtl.DTLVardef@133c6bd_HPS_FORMAT_FIGEXP M_FIG The use of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from Duchenne muscular dystrophy (DMD) patients to model cardiomyopathic features in DMD and unravel novel pathological mechanistic insights. DMD iPSC-CMs showed accelerated cell death, caused by increased intracellular reactive oxygen species (ROS) levels. By intervention at different target sites, beneficial effects on the mitochondrial membrane potential ({Delta}{Psi}m) and the expression and ROS-producing activity of the cardiac-specific NADPH-oxidase 4 isoform (NOX4) were observed, resulting in an increased cell survival and function of DMD iPSC-CMs. C_FIG

developmental biology↗