Background Multisystem inflammatory syndrome in children associated with COVID-19 (MIS-C) causes significant cardiovascular involvement, which can be a determinant of clinical course and outcome. We aimed to investigate whether echocardiographic measures of ventricular function were independently associated with adverse clinical course and cardiac sequaele in MIS-C. Methods In a longitudinal observational study of 54 MIS-C patients (mean age 6.8 ± 4.4 years, 46% male, 56% African American), measures of ventricular function and morphometry at initial presentation, pre-discharge, and median of 3 and 10 week follow-up were retrospectively analyzed, and were compared to 108 84 age and gender matched normal controls. The magnitude of strain is expressed as an absolute value. Risk stratification for adverse clinical course and outcomes were analyzed between the tertiles of clinical and echo data using ANOVA, univariate and multivariate regression. Results Median LV apical 4-chamber longitudinal (LVA4LS) and global longitudinal strain (LVGLS) at the initial presentation were significantly decreased in MIS-C compared to normal cohort (16.2% and 15.1% vs. 22.3% and 22.0% respectively, p<0.01). Patients in the lowest LVA4LS tertile (<13%) had significantly higher CRP and hs-Troponin, need for intensive care (ICU), mechanical life support, and longer hospital length of stay (LOS) compared to those in the highest tertile (>18.5%) (p<0.01). Initial LVA4LS and LVGLS were normal in 13 of 54 and 10 of 39 patients respectively. There was no mortality. In multivariate regression, only LVA4LS was associated with both the need for ICU and LOS. At median 10 week follow-up to date, 7 of 36 patients (19%) and 6 of 25 patients (24%) had abnormal LVA4LS and LVGLS respectively. Initial LVA4LS<16.2% indicated abnormal LVA4LS at follow-up with 100% sensitivity. Conclusion Impaired LVGLS and LVA4LS at initial presentation independently indicate a higher risk of adverse acute clinical course and persistent subclinical LV dysfunction at 10 weeks follow-up, suggesting they could be applied to identify higher risk children with MIS-C.

. Inhibition of crossbridge formation has no effect on contraction-associated phosphorylation of p38 MAPK in mouse skeletal muscle. Am J Physiol Cell Physiol 288: C824 -C830, 2005. First published December 1, 2004; doi:10.1152/ajpcell.00500.2004.-Mitogen-activated protein kinases (MAPKs), in particular p38 MAPK, are phosphorylated in response to contractile activity, yet the mechanism for this is not understood. We tested the hypothesis that the force of contraction is responsible for p38 MAPK phosphorylation in skeletal muscle. Extensor digitorum longus (EDL) muscles isolated from adult male Swiss Webster mice were stimulated at fixed length at 10 Hz for 15 min and then subjected to Western blot analysis for the phosphorylation of p38 MAPK and ERK1/2. Contralateral muscles were fixed at resting length and were not stimulated. Stimulated muscles showed a 2.5-fold increase in phosphorylated p38 MAPK relative to nonstimulated contralateral controls, and there was no change in the phosphorylation of ERK1/2. When contractile activity was inhibited with N-benzyl-p-toluene sulfonamide (BTS), a specific inhibitor of actomyosin ATPase, force production decreased in both a time-and concentration-dependent manner. Preincubation with 25, 75, and 150 M BTS caused 78 Ϯ 4%, 97 Ϯ 0.2%, and 99 Ϯ 0.2% inhibition in contractile force, respectively, and was stable after 30 min of treatment. Fluorescence measurements demonstrated that Ca 2ϩ cycling was minimally affected by BTS treatment. Surprisingly, BTS did not suppress the level of p38 MAPK phosphorylation in stimulated muscles. These data do not support the view that force generation per se activates p38 MAPK and suggest that other events associated with contraction must be responsible.calcium; energetics; mechanical stress; metabolism MAMMALIAN MUSCLE CELLS EXHIBIT a remarkable adaptive capacity to modify phenotype in response to environmental and metabolic stress. Cardiac, smooth, and skeletal muscles all respond to increased mechanical loading by hypertrophic growth (i.e., increased fiber diameter) (3,4,6,13,28,29,31,36,37). Additional adaptations to functional demands are based on the nature and duration of the imposed load. Mitochondrial density, metabolic enzymes, and tissue capillarity all increase when muscles are subjected to elevations in the duty cycle for extended periods (16). Conversely, a decrease in the duty cycle results in adaptive changes in phenotype in the opposite direction (4). Despite the extensive catalog of information on the genetic and morphological changes that occur through changes in activity or loading, the intracellular signals and the transduction pathways that couple them to transitions in phenotype are still not well understood.Several signaling cascades involving families of mitogenactivated protein kinases (MAPKs) are responsive to mechanical stress in smooth, skeletal, and myocardial muscle (1,9,17,23,24,26,30,36,38,39,42,43). These include extracellular signal-regulated kinase (ERK)1/2, c-Jun NH 2 -terminal kinase (JNK), and p38 MAPK an...

Muscle contractions strongly activate p38 MAP kinases, but the precise contraction-associated sarcoplasmic event(s) (e.g. force production, energetic demands and/or calcium cycling) that activate these kinases are still unclear. We tested the hypothesis that during contraction the phosphorylation of p38 isoforms is sensitive to the increase in ATP demand relative to ATP supply. Energetic demands were inhibited using N-benzyl-p-toluene sulphonamide (BTS, type II actomyosin) and cyclopiazonic acid (CPA, SERCA). Extensor digitorum longus muscles from Swiss Webster mice were incubated in Ringer’s solution (37°C) with or without inhibitors and then stimulated at 10 Hz for 15 min. Muscles were immediately freeze-clamped for metabolite and western blot analysis. BTS and BTS+CPA treatment decreased force production by 85%, as measured by the tension time integral, while CPA alone potentiated force by 310%. In control muscles, contractions resulted in a 73% loss of ATP content and a concomitant 7-fold increase in IMP content, a measure of sustained energetic imbalance. BTS or CPA treatment lessened the loss of ATP, but BTS+CPA treatment completely eliminated the energetic imbalance since ATP and IMP levels were nearly equal to those of non-stimulated muscles. The independent inhibition of cytosolic ATPase activities had no effect on contraction-induced p38 MAPK phosphorylation, but combined treatment prevented the increase in phosphorylation of the γ isoform while the α/βisoforms unaffected. These observations suggest that an energetic signal may trigger phosphorylation of the p38γ isoform while other factors are involved in activating the α/β isoforms, and also may explain how contractions differentially activate signaling pathways.

Early reports suggested that pediatric COVID-19 cases were less severe in children. Most children requiring intensive care admission in these reports had underlying medical conditions. Shortly after the surge of adult COVID-19 cases in Detroit, Michigan, previously healthy children began to present with shock with multiorgan dysfunction, elevated inflammatory markers, and physical exam findings with features of Kawasaki disease. This disease process was later called multisystem inflammatory syndrome in children (MIS-C.) In this case series, we describe three previously healthy children who presented with severe manifestations of MIS-C, including cardiogenic shock and profound systemic inflammation. These children developed severely depressed myocardial function with end-organ injury and were cannulated to veno-arterial extracorporeal membrane oxygenation (VA-ECMO) due to cardiogenic shock with arrhythmia. All three children improved with VA-ECMO support and anti-inflammatory treatment. All had complete recovery of myocardial function at discharge and 6-month follow-up with no significant morbidity.