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Washington, DC, United States

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News Article | May 17, 2017
Site: www.sciencedaily.com

Weekly doses of glucocorticoid steroids, such as prednisone, help speed recovery in muscle injuries, reports a new Northwestern Medicine study. The weekly steroids also repaired muscles damaged by muscular dystrophy. The studies were conducted in mice, with broad implications for humans. One of the major problems of using steroids such as prednisone is they cause muscle wasting and weakness when taken long term. This is a significant problem for people who take steroids for many chronic conditions, and can often result in patients having to stop steroid treatments. But the new study in mice showed weekly doses -- rather than daily ones -- promote muscle repair. "We don't have human data yet, but these findings strongly suggest some alternative ways of giving a very commonly used drug in a manner that doesn't harm, but in fact helps muscle," said lead investigator Dr. Elizabeth McNally, the Elizabeth J. Ward Professor of Genetic Medicine at Northwestern University Feinberg School of Medicine and a Northwestern Medicine physician. McNally also is the director of the Center for Genetic Medicine at Feinberg. The study was published online in May in the Journal of Clinical Investigation. The study showed prednisone directs the production of annexins, proteins that stimulate muscle healing. Giving weekly doses of prednisone also stimulated a molecule called KLF15, which is associated with improved muscle performance. Daily doses of prednisone, however, reduced KLF15, leading to muscle wasting. In the study, normal mice with a muscle injury received steroids just before injury and for two weeks after the injury. Mice receiving two weekly doses of steroids after the injury performed better on treadmill testing and had stronger muscle than mice receiving a placebo. Mice that received daily steroids for two weeks after the muscle injury performed poorly on the treadmill and in muscle strength studies, compared to placebo-treated mice. Scientists also tested the drug in a mouse model of muscular dystrophy, since prednisone is normally given for this disease. Mice with muscular dystrophy that received weekly prednisone were stronger and performed better on the treadmill than those getting a placebo. When prednisone was given every day, the muscles atrophied and wasted. McNally initiated the research because she wanted to understand how prednisone -- which is given to treat individuals with a form of muscular dystrophy called Duchenne Muscular Dystrophy -- prolongs patients' ability to walk independently and stay out of a wheelchair. "It's been known that long-term daily treatment with prednisone also has the side effect of causing muscle wasting in many people," McNally said. "So it has always been something of a medical curiosity that it is also used chronically to treat conditions like myositis (muscle inflammation) and Duchenne Muscular Dystrophy. " While years of being on the steroids cause growth suppression, osteoporosis and other bad side effects, boys with Duchenne Muscular Dystrophy walk two to three years longer if they take steroids. Boys get the disease because it is on the X chromosome, and males have only one X chromosome. "A typical boy with Duchenne Muscular Dystrophy goes into a wheelchair at age 10; if he takes steroids, it's age 13," McNally said. "So in muscular dystrophy, there is definitely a benefit, but it's a double-edged sword with all the side effects." For the study, McNally and colleagues used high-resolution imaging to view the muscle's ability to repair itself. This technique uses a laser to poke a hole in muscle cells. Then the muscle cell is observed in real time as it reseals the hole, a natural repair process. Next, the scientists tested to see if steroids could boost the repair process. "The steroids made muscle heal faster," McNally said. "We were like, 'Wow!' It accelerated the repair in the muscle cells." For the second part of the study, scientists tested steroids in mice. They damaged the leg muscles in mice and noticed the mice receiving the steroids recovered more rapidly from injury. "We showed steroid treatment, when given weekly, improves muscle performance," McNally said. Her work also implies normal muscle injury would improve more quickly by taking a weekly dose of steroids such as prednisone. In the future, McNally would like to test steroids in humans and is considering studying it in forms of muscular dystrophy in which steroids would not normally be given, like Becker Muscular Dystrophy or Limb Girdle Muscular Dystrophy. Steroid treatment is not usually offered for these diseases since the side effects are thought to outweigh any potential benefit.


News Article | May 16, 2017
Site: www.eurekalert.org

Steroids thought to waste muscles surprisingly turn out to be beneficial in weekly doses CHICAGO --- Weekly doses of glucocorticoid steroids, such as prednisone, help speed recovery in muscle injuries, reports a new Northwestern Medicine study. The weekly steroids also repaired muscles damaged by muscular dystrophy. The studies were conducted in mice, with broad implications for humans. One of the major problems of using steroids such as prednisone is they cause muscle wasting and weakness when taken long term. This is a significant problem for people who take steroids for many chronic conditions, and can often result in patients having to stop steroid treatments. But the new study in mice showed weekly doses -- rather than daily ones -- promote muscle repair. "We don't have human data yet, but these findings strongly suggest some alternative ways of giving a very commonly used drug in a manner that doesn't harm, but in fact helps muscle," said lead investigator Dr. Elizabeth McNally, the Elizabeth J. Ward Professor of Genetic Medicine at Northwestern University Feinberg School of Medicine and a Northwestern Medicine physician. McNally also is the director of the Center for Genetic Medicine at Feinberg. The study was published online in May in the Journal of Clinical Investigation. The study showed prednisone directs the production of annexins, proteins that stimulate muscle healing. Giving weekly doses of prednisone also stimulated a molecule called KLF15, which is associated with improved muscle performance. Daily doses of prednisone, however, reduced KLF15, leading to muscle wasting. In the study, normal mice with a muscle injury received steroids just before injury and for two weeks after the injury. Mice receiving two weekly doses of steroids after the injury performed better on treadmill testing and had stronger muscle than mice receiving a placebo. Mice that received daily steroids for two weeks after the muscle injury performed poorly on the treadmill and in muscle strength studies, compared to placebo-treated mice. Scientists also tested the drug in a mouse model of muscular dystrophy, since prednisone is normally given for this disease. Mice with muscular dystrophy that received weekly prednisone were stronger and performed better on the treadmill than those getting a placebo. When prednisone was given every day, the muscles atrophied and wasted. McNally initiated the research because she wanted to understand how prednisone -- which is given to treat individuals with a form of muscular dystrophy called Duchenne Muscular Dystrophy -- prolongs patients' ability to walk independently and stay out of a wheelchair. "It's been known that long-term daily treatment with prednisone also has the side effect of causing muscle wasting in many people," McNally said. "So it has always been something of a medical curiosity that it is also used chronically to treat conditions like myositis (muscle inflammation) and Duchenne Muscular Dystrophy. " While years of being on the steroids cause growth suppression, osteoporosis and other bad side effects, boys with Duchenne Muscular Dystrophy walk two to three years longer if they take steroids. Boys get the disease because it is on the X chromosome, and males have only one X chromosome. "A typical boy with Duchenne Muscular Dystrophy goes into a wheelchair at age 10; if he takes steroids, it's age 13," McNally said. "So in muscular dystrophy, there is definitely a benefit, but it's a double-edged sword with all the side effects." For the study, McNally and colleagues used high-resolution imaging to view the muscle's ability to repair itself. This technique uses a laser to poke a hole in muscle cells. Then the muscle cell is observed in real time as it reseals the hole, a natural repair process. Next, the scientists tested to see if steroids could boost the repair process. "The steroids made muscle heal faster," McNally said. "We were like, 'Wow!' It accelerated the repair in the muscle cells." For the second part of the study, scientists tested steroids in mice. They damaged the leg muscles in mice and noticed the mice receiving the steroids recovered more rapidly from injury. "We showed steroid treatment, when given weekly, improves muscle performance," McNally said. Her work also implies normal muscle injury would improve more quickly by taking a weekly dose of steroids such as prednisone. In the future, McNally would like to test steroids in humans and is considering studying it in forms of muscular dystrophy in which steroids would not normally be given, like Becker Muscular Dystrophy or Limb Girdle Muscular Dystrophy. Steroid treatment is not usually offered for these diseases since the side effects are thought to outweigh any potential benefit. The study was funded in part by National Institutes of Health grants NIH U54 AR052646 and NIH RO1 NS047726, the Muscular Dystrophy Association, Parent Project Muscular Dystrophy and the American Heart Association.


Lanctot A.,Center for Genetic Medicine | Lanctot A.,Northwestern University | Pawlisz A.,Center for Genetic Medicine | Joksimovic M.,Center for Genetic Medicine | And 2 more authors.
Developmental Cell | Year: 2013

Regulating cell proliferation and differentiation in CNS development requires both extraordinary complexity and precision. Neural progenitors receive graded overlapping signals from midline signaling centers, yet each makes a unique cell fate decision in a spatiotemporally restricted pattern. The Nde1-Lis1 complex regulates individualized cell fate decisions based on the geographical location with respect to the midline. While cells distant from the midline fail to self-renew in the Nde1-Lis1 double-mutant CNS, cells embedded in the signaling centers showed marked overproliferation. A direct interaction between Lis1 and Brap, a mitogen-activated protein kinase (MAPK) signaling threshold modulator, mediates this differential response to mitogenic signal gradients. Nde1-Lis1 deficiency resulted in a spatially dependent alteration of MAPK scaffold Ksr and hyperactivation of MAPK. Epistasis analyses supported synergistic Brap and Lis1 functions. These results suggest that a molecular complex composed of Nde1, Lis1, and Brap regulates the dynamic MAPK signaling threshold in a spatially dependent fashion. © 2013 Elsevier Inc.


Joyce N.C.,University of California at Davis | Hache L.P.,Center for Genetic Medicine | Clemens P.R.,University of Pittsburgh
Physical Medicine and Rehabilitation Clinics of North America | Year: 2012

This article reviews the recent literature regarding bone health as it relates to the patient living with neuromuscular disease (NMD). Studies defining the scope of bone-related disease in NMD are scant. The available evidence is discussed, focusing on abnormal calcium metabolism, increased fracture risk, and the prevalence of both scoliosis and hypovitaminosis D in Duchenne muscular dystrophy, amyotrophic lateral sclerosis, and spinal muscular atrophy. Future directions are discussed, including the urgent need for studies both to determine the nature and extent of poor bone health, and to evaluate the therapeutic effect of available osteoporosis treatments in patients with NMD. © 2012 Elsevier Inc.


Balanescu S.,Hospital Center | Kopp P.,Center for Genetic Medicine | Gaskill M.B.,Northwestern University | Morgenthaler N.G.,M.R.Research | And 3 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Background: Copeptin, the C-terminal moiety of provasopressin, is cosecreted with vasopressin. Copeptin may be a useful parameter to characterize disorders of water homeostasis and can be readily measured in plasma or serum. However, it is unknown to datehowcirculating copeptin and vasopressin levels correlate at different plasma osmolalites. Objective: To correlate plasma copeptin with plasma osmolality and vasopressin concentrations in healthy subjects during iso-, hypo-, and hyperosmolar states. Methods: Plasma osmolalities, copeptin, and vasopressin levels were measured in 20 volunteers at baseline, after an oral water load, and during and after iv infusion of 3% saline. Correlation coefficients were determined between plasma osmolalites and copeptin and vasopressin concentrations, as well as between vasopressin and copeptin concentrations. Results: Median plasma osmolalities decreased from 290 mOsm/kg (range, 284-302) at baseline to 281 (273-288) mOsm/kg after water load and rose to 301 (298-307) mOsm/kg after hypertonic saline. Median plasma copeptin concentrations decreased from 3.3 (1.1-36.4) pM at baseline to 2.0 (0.9 -10.4) pM after water load and increased to 13.6 (3.7- 43.3) pM after hypertonic saline. Vasopressin and copeptin concentrations correlated with plasma osmolality (Spearman's rank correlation coefficient 0.49 and 0.77, respectively). There was a close correlation of vasopressin and copeptin concentrations (Spearman's rank correlation coefficient 0.8). Conclusion: Plasma vasopressin and copeptin correlate strongly over a wide range of osmolalities in healthy individuals. Therefore, the measurement of copeptin, which remains stable for several days, is a useful alternative to vasopressin measurements and will likely facilitate the differential diagnosis of disorders of water metabolism. Copyright © 2011 by The Endocrine Society.


Kim S.-Y.,Northwestern University | Cordeiro M.H.,Northwestern University | Serna V.A.,Center for Genetic Medicine | Ebbert K.,Northwestern University | And 5 more authors.
Cell Death and Differentiation | Year: 2013

Non-proliferating oocytes within avascular regions of the ovary are exquisitely susceptible to chemotherapy. Early menopause and sterility are unintended consequences of chemotherapy, and efforts to understand the oocyte apoptotic pathway may provide new targets for mitigating this outcome. Recently, the c-Abl kinase inhibitor imatinib mesylate (imatinib) has become the focus of research as a fertoprotective drug against cisplatin. However, the mechanism by which imatinib protects oocytes is not fully understood, and reports of the drug's efficacy have been contradictory. Using in vitro culture and subrenal grafting of mouse ovaries, we demonstrated that imatinib inhibits the cisplatin-induced apoptosis of oocytes within primordial follicles. We found that, before apoptosis, cisplatin induces c-Abl and TAp73 expression in the oocyte. Oocytes undergoing apoptosis showed downregulation of TAp63 and upregulation of Bax. While imatinib was unable to block cisplatin-induced DNA damage and damage response, such as the upregulation of p53, imatinib inhibited the cisplatin-induced nuclear accumulation of c-Abl/TAp73 and the subsequent downregulation of TAp63 and upregulation of Bax, thereby abrogating oocyte cell death. Surprisingly, the conditional deletion of Trp63, but not ΔNp63, in oocytes inhibited apoptosis, as well as the accumulation of c-Abl and TAp73 caused by cisplatin. These data suggest that TAp63 is the master regulator of cisplatin-induced oocyte death. The expression kinetics of TAp63, c-Abl and TAp73 suggest that cisplatin activates TAp63-dependent expression of c-Abl and TAp73 and, in turn, the activation of TAp73 by c-Abl-induced BAX expression. Our findings indicate that imatinib protects oocytes from cisplatin-induced cell death by inhibiting c-Abl kinase, which would otherwise activate TAp73-BAX-mediated apoptosis. Thus, imatinib and other c-Abl kinase inhibitors provide an intriguing new way to halt cisplatin-induced oocyte death in early follicles and perhaps conserve the endocrine function of the ovary against chemotherapy. © 2013 Macmillan Publishers Limited All rights reserved.


An E.,Center for Genetic Medicine | An E.,George Washington University | Sen S.,Center for Genetic Medicine | Park S.K.,Scripps Research Institute | And 2 more authors.
Investigative Ophthalmology and Visual Science | Year: 2010

Purpose. To define the role of the serine protease HTRA1 in age-related macular degeneration (AMD) by examining its expression level and identifying its potential substrates in the context of primary RPE cell extracellular milieu. Methods. Primary RPE cell cultures were established from human donor eyes and screened for CFH, ARMS2, and HTRA1 risk genotypes by using an allele-discrimination assay. HTRA1 expression in genotyped RPE cells was determined by using real-time PCR and quantitative proteomics. Potential HTRA1 substrates were identified by incubating RPE-conditioned medium with or without human recombinant HTRA1. Selectively cleaved proteins were quantified by using the differential stable isotope labeling by amino acids in cell culture (SILAC) strategy. Results. HTRA1 mRNA levels were threefold higher in primary RPE cells homozygous for the HTRA1 promoter risk allele than in RPE cells with the wild-type allele, which translated into a twofold increase in HTRA1 secretion by RPE cells with the risk genotype. A total of 196 extracellular proteins were identified in the RPE secretome, and only 8 were found to be selectively cleaved by the human recombinant HTRA1. These include fibromodulin with 90% cleavage, clusterin (50%), ADAM9 (54%), vitronectin (54%), and a2-macroglobulin (55%), as well as some cell surface proteins including talin-1 (21%), fascin (40%), and chloride intracellular channel protein 1 (51%).Conclusions. Recombinant HTRA1 cleaves RPE-secreted proteins involved in regulation of the complement pathway (clusterin, vitronectin, and fibromodulin) and of amyloid deposition (clusterin, α2-macroglobulin, and ADAM9). These findings suggest a link between HTRA1, complement regulation, and amyloid deposition in AMD pathogenesis. © Association for Research in Vision and Ophthalmology.


Demonbreun A.R.,Center for Genetic Medicine | Biersmith B.H.,Center for Genetic Medicine | McNally E.M.,Center for Genetic Medicine
Seminars in Cell and Developmental Biology | Year: 2015

Mature skeletal muscle forms from the fusion of skeletal muscle precursor cells, myoblasts. Myoblasts fuse to other myoblasts to generate multinucleate myotubes during myogenesis, and myoblasts also fuse to other myotubes during muscle growth and repair. Proteins within myoblasts and myotubes regulate complex processes such as elongation, migration, cell adherence, cytoskeletal reorganization, membrane coalescence, and ultimately fusion. Recent studies have identified cell surface proteins, intracellular proteins, and extracellular signaling molecules required for the proper fusion of muscle. Many proteins that actively participate in myoblast fusion also coordinate membrane repair. Here we will review mammalian membrane fusion with specific attention to proteins that mediate myoblast fusion and muscle repair. © 2015 Elsevier Ltd.


Ah Mew N.,Center for Genetic Medicine | Ah Mew N.,George Washington University | Krivitzky L.,Children's Hospital of Philadelphia | McCarter R.,Center for Genetic Medicine | And 5 more authors.
Journal of Pediatrics | Year: 2013

Objective: To compare the clinical course and outcome of patients diagnosed with one of 4 neonatal-onset urea cycle disorders (UCDs): deficiency of carbamyl phosphate synthase 1 (CPSD), ornithine transcarbamylase (OTCD), argininosuccinate synthase (ASD), or argininosuccinate lyase (ALD). Study design: Clinical, biochemical, and neuropsychological data from 103 subjects with neonatal-onset UCDs were derived from the Longitudinal Study of Urea Cycle Disorders, an observational protocol of the Urea Cycle Disorders Consortium, one of the Rare Disease Clinical Research Networks. Results: Some 88% of the subjects presented clinically by age 7 days. Peak ammonia level was 963 μM in patients with proximal UCDs (CPSD or OTCD), compared with 589 μM in ASD and 573 μM in ALD. Roughly 25% of subjects with CPSD or OTCD, 18% of those with ASD, and 67% of those with ALD had a "honeymoon period," defined as the time interval from discharge from initial admission to subsequent admission for hyperammonemia, greater than 1 year. The proportion of patients with a poor outcome (IQ/Developmental Quotient <70) was greatest in ALD (68%), followed by ASD (54%) and CPSD/OTCD (47%). This trend was not significant, but was observed in both patients aged <4 years and those aged ≥4 years. Poor cognitive outcome was not correlated with peak ammonia level or duration of initial admission. Conclusion: Neurocognitive outcomes do not differ between patients with proximal UCDs and those with distal UCDs. Factors other than hyperammonemia may contribute to poor neurocognitive outcome in the distal UCDs. Copyright © 2013 Mosby Inc.


Pajoohesh-Ganji A.,George Washington University | Knoblach S.M.,Center for Genetic Medicine | Faden A.I.,University of Maryland Baltimore County | Byrnes K.R.,Uniformed Services University of the Health Sciences
Brain Research | Year: 2012

Inflammation has long been implicated in secondary tissue damage after spinal cord injury (SCI). Our previous studies of inflammatory gene expression in rats after SCI revealed two temporally correlated clusters: the first was expressed early after injury and the second was up-regulated later, with peak expression at 1-2 weeks and persistent up-regulation through 6 months. To further address the role of inflammation after SCI, we examined inflammatory genes in a second species, mice, through 28 days after SCI. Using anchor gene clustering analysis, we found similar expression patterns for both the acute and chronic gene clusters previously identified after rat SCI. The acute group returned to normal expression levels by 7 days post injury. The chronic group, which included C1qB, p22phox and galectin-3, showed peak expression at 7 days and remained up-regulated through 28 days. Immunohistochemistry and western blot analysis showed that the protein expression of these genes was consistent with the mRNA expression. Further exploration of the role of one of these genes, galectin-3, suggests that galectin-3 may contribute to secondary injury. In summary, our findings extend our prior gene profiling data by demonstrating the chronic expression of a cluster of microglial associated inflammatory genes after SCI in mice. Moreover, by demonstrating that inhibition of one such factor improves recovery, the findings suggest that such chronic up-regulation of inflammatory processes may contribute to secondary tissue damage after SCI, and that there may be a broader therapeutic window for neuroprotection than generally accepted. © 2012 Elsevier B.V. All rights reserved.

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