Anti-MEF2C monoclonal antibody, clone 7I3H3

Cellular therapies for the treatment of myocardial infarction have proven to be an invaluable tool in recent years and provide encouraging evidence for the possibility to restore normal heart function. However, questions still remain as to the optimal cell source, pre-conditioning methods and delivery techniques for such an application. This study explores the use of a population of stem cells arising from the neural crest and isolated from adult human periodontal ligament along with short-term mechanical strain as an inducer of cardiomyogenesis and possibly pre-conditioning stimulus for cellular cardiomyoplasty. Cells were subjected to a short-term dynamic mechanical tension in our custom-built bioreactor and analyzed for cardiomyogenic commitment. Mechanical strain elicited a cardiomyogenic response from the cells following just 2 h of stimulation. Mechanical strain activated and translocated cardiac-specific transcription factors GATA4, MEF2C and Nkx2.5, and induced expression of the sarcomeric actin and cardiac troponin T proteins. Mechanical strain induced production of significantly higher levels of nitric oxide when compared to static controls. Elimination of elevated ROS levels by free radical scavengers completely abolished the cardiomyogenic response of the cells. MicroRNA profile changes in stretched cells were detected for 39 miRNAs with 16 of the differentially expressed miRNAs related to heart development. The use of stem cells in combination with mechanical strain prior to their delivery in vivo may pose a valuable alternative for the treatment of myocardial infarction and merits further exploration for its capacity to augment the already observed beneficial effects of cellular therapies.

Skeletal muscle represents the largest pool of body zinc, however, little is known about muscle zinc homeostasis or muscle-specific zinc functions. Zip14 (Slc39a14) was the most highly expressed zinc transporter in skeletal muscle of mice in response to LPS-induced inflammation. We compared metabolic parameters of skeletal muscle from global Zip14 knockout (KO) and wild-type mice (WT). At basal steady state Zip14 KO mice exhibited a phenotype that included muscle wasting and metabolic endotoxemia. Microarray and qPCR analysis of gastrocnemius muscle RNA revealed that ablation of Zip14 produced increased muscle p-Mef2c, Hspb7 and miR-675-5p expression and increased p38 activation. ChIP assays showed enhanced binding of NF-kappa beta to the Mef2c promoter. In contrast, LPS-induced systemic inflammation enhanced Zip14-dependent zinc uptake by muscle, increased expression of Atrogin1 and MuRF1 and markedly reduced MyoD. These signatures of muscle atrophy and cachexia were not influenced by Zip14 ablation, however. LPS-induced miR-675-3p and -5p expression was Zip14-dependent. Collectively, these results with an integrative model are consistent with a Zip14 function in skeletal muscle at steady state that supports myogenesis through suppression of metabolic endotoxemia and that Zip14 ablation coincides with sustained activity of phosphorylated components of signaling pathways including p-Mef2c, which causes Hspb7-dependent muscle wasting.