ACID SPHINGOMYELINASE AS A NEW PHARMACOLOGICAL TARGET IN THE ACUTE AND CHRONIC MUSCLE DAMAGE: AN ALTERNATIVE STRATEGY FOR MUSCULAR DYSTROPHIES THERAPY
Creators: name: DI RENZO, ILARIA
Publisher: name: Universit� degli Studi di Milano
Year: 2018

description: Skeletal muscle inflammation plays a critical role in bridging early muscle injury responses and timely muscle injury recovery (Yang and Hu, 2018). In this study, we investigated the functional role of the sphingolipid-metabolizing enzyme Acid Sphingomyelinase (A-SMase) in the pathophysiology of acute and chronic muscle damage in order to elucidate its role in the establishment of inflammation and in the subsequent muscle regeneration process so that this protein may be proposed as possible therapeutic target. A-SMase is a critical mediator of cell signaling since it is able to generate ceramide from the membrane lipid sphingomyelin thus modulating membrane fluidity, which is determinant in triggering many cellular processes. Several recent studies report the strong relation between high levels of A-SMase expression and inflammatory-associated disorders (Schissel et al., 1998; Devlin et al., 2008; Garcia-Ruiz et al., 2015). In this study, we found that A-SMase expression increases upon induced-acute muscle damage suggesting its involvement in skeletal muscle inflammation. We also demonstrated the importance of A-SMase in regulating the muscle regeneration process following acute muscle damage. Our results showed that A-SMase deficiency leads to an increase of muscle satellite cells, essential for skeletal muscle regeneration, soon after injury, accompanied by a higher number of regenerating myofibers within the injured site. Moreover, two important muscle transcription factors, MyoD and Myogenin, responsible for a correct regeneration were much higher in the absence of A-SMase suggesting that muscle regeneration is accelerated without the hydrolase. In addition, IGF-1, a potent enhancer of tissue regeneration, showed much higher expression levels in absence of A-SMase, consistently with our finding that A-SMase deficiency accelerates the regeneration process. Furthermore, we provide the first evidence of a novel role of A-SMase in regulating macrophage subsets during muscle regeneration demonstrating that A-SMase is able to regulate the polarization of macrophages towards an inflammatory M1 phenotype since its absence leads to an impairment in the expression of M1 macrophage markers. Noteworthy, investigating the role of A-SMase in mdx mice, a mouse model of Duchenne Muscular Dystrophy (DMD), we found an up-regulation of A-SMase in expression and activity in muscles of these mice, that implies its involvement in the pathogenesis of DMD with a particular effect on inflammation. Several studies demonstrated a predominant role of inflammation in the pathogenesis of DMD (Villalta et al., 2009; Radley et al., 2008). Of notice, we observed that the increase of A- SMase in mdx mice paralleled with the increase of muscle inflammatory state. This finding has been further corroborated by the use of the anti-inflammatory drug Naproxcinod that reduced inflammation in mdx muscle and at the same time significantly decreased A-SMase expression and activity. Altogether, our findings open new vistas in the identification of a new potential pharmacological target, A-SMase, in the development and regulation of skeletal muscle inflammation and regeneration process by raising the possibility that the modulation of A-SMase expression levels could bring therapeutic benefits not only in DMD pathology but also in various muscle-wasting diseases.