X-linked myotubular myopathy (XLMTM) is a congenital disorder caused by mutations of the myotubularin gene, MTM1. Myotubularin belongs to a large family of conserved lipid phosphatases that include both catalytically active and inactive myotubularin-related proteins (i.e., “MTMRs”). Biochemically, catalytically inactive MTMRs have been shown to form heteroligomers with active members within the myotubularin family through protein-protein interactions. However, the pathophysiological significance of catalytically inactive MTMRs remains unknown in muscle. By in vitro as well as in vivo studies, we have identified that catalytically inactive myotubularin-related protein 12 (MTMR12) binds to myotubularin in skeletal muscle. Knockdown of the mtmr12 gene in zebrafish resulted in skeletal muscle defects and impaired motor function. Analysis of mtmr12 morphant fish showed pathological changes with central nucleation, disorganized Triads, myofiber hypotrophy and whorled membrane structures similar to those seen in X-linked myotubular myopathy. Biochemical studies showed that deficiency of MTMR12 results in reduced levels of myotubularin protein in zebrafish and mammalian C2C12 cells. Loss of myotubularin also resulted in reduction of MTMR12 protein in C2C12 cells, mice and humans. Moreover, XLMTM mutations within the myotubularin interaction domain disrupted binding to MTMR12 in cell culture. Analysis of human XLMTM patient myotubes showed that mutations that disrupt the interaction between myotubularin and MTMR12 proteins result in reduction of both myotubularin and MTMR12. These studies strongly support the concept that interactions between myotubularin and MTMR12 are required for the stability of their functional protein complex in normal skeletal muscles. This work highlights an important physiological function of catalytically inactive phosphatases in the pathophysiology of myotubular myopathy and suggests a novel therapeutic approach through identification of drugs that could stabilize the myotubularin-MTMR12 complex and hence ameliorate this disorder.

The aim of this study was to characterize the outcomes of traumatic abdominal and pelvic vascular injuries. Using the 2012 National Trauma Data Bank, we identified 5858 patients with major abdominal and/or pelvic vascular injury. Patients were stratified by age group, gender, race, Injury Severity Score (ISS), and mechanism of injury. We evaluated the percentage of patients with blunt and penetrating trauma by demographic and correlated the mechanism of injury to the ISS score, emergency room disposition, and hospital disposition. We performed a logistic regression analysis to calculate predictors of death. In the final cohort, 1458 patients (25%) with abdominal/pelvic vascular injury died of trauma. In total, 3368 patients (57%) had a blunt mechanism of injury, whereas 2353 (40%) were victims of a penetrating trauma. Patients with penetrating injuries were 1.72 times more likely to die from their injuries than those with blunt traumas. Patients with higher ISS scores (>16) were more likely to die from their injuries than patients with lower ISS scores. Men were more likely to experience a penetrating vascular injury than women (48% vs 17%). Similarly, 77 per cent of black patients had a penetrating mechanism of injury compared with 20 per cent of white patients. There were 1910 patients with penetrating injuries (81%) that went immediately from the emergency room to the OR, compared with 1287 patients with blunt injuries (38%). Of the patients with blunt injuries, 695 (21%) died, whereas 727 (31%) patients with penetrating injuries died. Abdominal and pelvic traumatic vascular injuries carry a high mortality rate. Penetrating mechanism of injury, ISS score, and race are independent predictors of mortality.

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