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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.

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.

Although antibiotic therapy has been the mainstay of prophylaxis and treatment of urinary tract infections (UTIs), antibacterial resistance has led to increased incidence of infections and healthcare spending in both community-acquired and nosocomial UTIs. This has led to an active exploration of alternative remedies for both the prophylaxis and treatment of UTIs, especially in women with recurrent urinary tract infections. Probiotic supplementation is one novel intervention that has been studied as a prophylactic measure in patients with UTIs. The current systematic review and meta-analysis was conducted to evaluate the efficacy of probiotics for prophylaxis in UTIs in premenopausal women. Detailed search strategies for each electronic database were developed for PubMed, EMBASE, and Scopus to identify relevant literature published between 2001-2021. RevMan 5.3 statistical software was used to analyze data in studies. The random-effects model was used for pooling the data. The risk of bias and study quality were assessed using Cochrane Collaboration's tool for assessing risk of bias in included studies. The scope of focus for this review was premenopausal adult women with a history of one or more UTI. The intervention consisted of a probiotic regimen for which the goal was to enhance the defensive microflora of the urogenital tract. Studies comparing a probiotic regimen to a placebo regimen were included. These studies' primary outcome was the proportion of women with at least one symptomatic bacterial UTI in each group (i.e., UTI recurrence rate) in the 12-month period following probiotic intervention. This study extends the work of researchers who systematically investigated the scientific literature on probiotics in the prevention of urinary tract infections with a particular focus on premenopausal women. After screening, three parallel-group randomized-controlled trials (RCTs) were included. We estimated the overall pooled data of these three studies with a total of 284 participants to have met the predefined inclusion criteria and were therefore included in this review. The results demonstrated that probiotics did not have a significant effect in the prophylaxis of UTIs. (Risk Ratio (RR): 0.59 confidence interval (CI): 0.26, 1.33), Heterogeneity: Chi² = 6.63, df = 2 ( = 0.04); I² =70%, Test for overall effect: Z = 1.27 ( = 0.20).  Conclusions Probiotics did not demonstrate a significant benefit in reducing UTI recurrence compared to placebo in premenopausal women. However, more conclusive data is needed to determine the effect that probiotics have on strengthening the urogenital microbial barrier against pathogenic bacteria and protecting against UTI recurrence.