Emerging roles of the myocardin family of proteins in lipid and glucose metabolism

Members of the myocardin family bind to the transcription factor serum response factor (SRF) and act as coactivators controlling genes of relevance for myogenic differentiation and motile function. Binding of SRF to DNA is mediated by genetic elements called CArG boxes, found often but not exclusively in muscle and growth controlling genes. Studies aimed at defining the full spectrum of these CArG elements in the genome (i.e. the CArGome) have in recent years, unveiled unexpected roles of the myocardin family proteins in lipid and glucose homeostasis. This coactivator family includes the protein myocardin (MYOCD), the myocardin-related transcription factors A and B (MRTF-A/MKL1 and MRTF-B/MKL2) and MASTR (MAMSTR). Here we discuss growing evidence that SRF-driven transcription is controlled by extracellular glucose through activation of the Rho-kinase pathway and actin polymerization. We also describe data showing that adipogenesis is influenced by MLK activity through actions upstream of peroxisome proliferator-activated receptor γ with consequences for whole body fat mass and insulin sensitivity. The recently demonstrated involvement of myocardin coactivators in the biogenesis of caveolae, Ω-shaped membrane invaginations of importance for lipid and glucose metabolism, is finally discussed. These novel roles of myocardin proteins may open the way for new unexplored strategies to combat metabolic diseases such as diabetes, which, at the current incidence, is expected to reach 333 million people worldwide by 2025. This review highlights newly discovered roles of myocardin-related transcription factors in lipid and glucose metabolism as well as novel insights into their well-established role as mediators of stretch-dependent effects in smooth muscle. As co-factors for serum response factor (SRF), MKLs regulates transcription of genes involved in the contractile function of smooth muscle cells. In addition to mechanical stimuli, this regulation has now been found to be promoted by extracellular glucose levels in smooth muscle. Recent reports also suggest that MKLs can regulate a subset of genes involved in the formation of lipid-rich invaginations in the cell membrane called caveolae. Finally, a potential role of MKLs in non-muscle cells has been discovered as they negatively influence adipocyte differentiation. (Figure presented.)

Patient outcomes after electrical injury – a retrospective study

Introduction People exposed to electrical injuries are often admitted to hospital for observation. Current evidence suggests that patients who have a normal ECG on admission after a low-voltage injury, with no loss of consciousness or initial cardiac arrest may be discharged home after a short observation time. Currently, there are no established standards for the duration of monitoring after electric shock, but 24 h of observation is the most commonly adopted approach. We carried out a retrospective study of patients admitted after electrical injuries to determine the in-hospital outcomes and 30-day mortality in these patients. Methods We performed a chart review of all patients with electrical injuries admitted to Østfold Hospital, Norway between the years 2001 and 2019, to determine in-hospital and 30-day mortality and the frequency of various cardiac and non-cardiac complications. Results Mean age of 465 included patients (88% males) was 31 years. Of all injuries, 329 (71%) were work-related, 17 (3.7%) involved loss of consciousness. Furthermore, 29/437 (6.6%) were high voltage (> 1000 V), and 243/401 (60.6%) were transthoracic injuries. 369 (79.4%) were discharged same day. None of the admitted patients died in hospital nor did any die within 30 days of admission, yielding a 30-day mortality of 0% (95% CI 0–0.8). At admission troponin was elevated in three (0.6%) patients, creatinine kinase (CK) in 30 (6.5%) and creatinine in six (1.3%). Electrocardiogram (ECG) abnormalities were described in 85 (18%) patients. No serious arrhythmias were detected. When comparing high- vs low-voltage or transthoracic vs other injuries, there were no significant differences between most of the outcomes, except for more ECG abnormalities in the transthoracic group, whereas more patients had elevated CK, and fewer discharged the same day in high-voltage injuries. Conclusion No in-hospital nor 30-day mortality or serious arrhythmias were encountered in those who were assessed, regardless of the type of injury. Troponin and creatinine were rarely elevated. It seems that conscious patients admitted with a normal ECG following a low-voltage injury may safely be discharged home after a quick clinical assessment including ECG

MicroRNA-dependent regulation of KLF4 by glucose in vascular smooth muscle

Diabetes is a major risk factor for cardiovascular disease and this is in part due to the effects of hyperglycemia on vascular smooth muscle cells. Small non-coding microRNAs are known to control smooth muscle phenotype and arterial contractility and are dysregulated in diabetes. The effect of microRNAs on smooth muscle differentiation is in part mediated by the transcription factor KLF4 but the role of this mechanism in diabetic vascular disease is not fully understood. Herein, we have investigated the importance of hyperglycemia and diabetes for the expression of KLF4 in vascular smooth muscle and the involvement of miRNAs in this regulation. Hyperglycemia down-regulated KLF4 in vascular smooth muscle cells and similar results were found in arteries of diabetic mice and patients. This correlated with a Foxa2-dependent up-regulation of miR-29c, which targeted KLF4 in vascular smooth muscle cells. Importantly, by preventing downregulation of KLF4, the induction of smooth muscle contractile protein markers by glucose was inhibited. In conclusion, miR-29 mediated inhibition of KLF4 in hyperglycemic conditions contributes to increased expression of contractile markers in vascular smooth muscle cells. Further studies are warranted to determine the therapeutic implications of miR-29 inhibition in diabetic vascular disease