Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The following parameters were measured and calculated in 124 consecutive muscle biopsies: mean fiber diameter, standard deviation, percentage of type I and Type II fibers, variability coefficient, hypertrophy and atrophy factor. Twenty percent of the histometrically analyzed biopsies showed a type II atrophy and four percent a type I atrophy. Type II atrophy was found particularly in the following disorders: collagen vascular diseases, steroid myopathies, cachexia and as a result of inactivity. Some neurogenic processes also demonstrated a selective type II atrophy. The combination of a grouped type II atrophy with a type I hypertrophy is characteristic of chronic and usually heredodegenerative disorders of the motoneurons. The presence of a selective type II atrophy argues against a genetically determined muscular dystrophy. A mixed atrophy classified here as strong or very strong primarily suggests a neuropathy. A selective type I hypertrophy has been found exclusively in neurogenic processes, and type II hypertrophy predominantly in the cases of chronic heredodegenerative neurogenic and primarily myopathic diseases. An increase of the variability coefficient of both types of muscle fibers is more frequent and pronounced in neurogenic processes than in myopathic syndromes. Type II fibers show a selective increase in the variability coefficient considerably more often than type I fibers. In contrast to other reports we seldom found a fiber type predominance or a pathological type-grouping. Only two out of five biopsies with pathological fiber type-grouping were definitely neurogenic. In special cases the histometric analysis of muscle fiber types improves the diagnostic efficiency of muscle biopsies.
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PMID:[Selective muscle fiber type anomalies in neuromusclar disorders. An analysis of 124 consecutive muscle biopsies (author's transl)]. 6 25

Improved muscle protein mass and increments in maximum voluntary muscle force have rarely been observed in men and women aged 60 years and older who were treated with rhGH. Although rhGH administration has been reported to increase lean body mass in older men and women, it is doubtful that this increase is localized to skeletal muscle contractile proteins. When rhGH administration was combined with 16 weeks of resistance exercises, increases in muscle mass, muscle protein synthesis, and muscle force were not greater in the rhGH-treated group than in a weight training group that received placebo injections. Side effects of rhGH treatment in elderly people are prevalent, not trivial, and further limit its usefulness as an effective anabolic agent for promoting muscle protein accretion in men and women. In particular, the induction of insulin resistance and carpal tunnel compression reduces the efficacy of rhGH replacement therapy in elderly individuals. The evidence for a GH-induced increase in human skeletal muscle protein and maximum voluntary muscle force is weak. The optimum dose and GH-replacement paradigm (GHRH, GH-secretagogues) have not been identified. Whether rhGH therapy improves muscle protein mass and force in individuals with severe cachexia associated with major trauma, burns, surgery, or muscular dystrophy is controversial and under investigation.
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PMID:Does growth hormone therapy in conjunction with resistance exercise increase muscle force production and muscle mass in men and women aged 60 years or older? 992 Jan 93

A human therapeutic that specifically modulates skeletal muscle growth would potentially provide a benefit for a variety of conditions including sarcopenia, cachexia, and muscular dystrophy. Myostatin, a member of the TGF-beta family of growth factors, is a known negative regulator of muscle mass, as mice lacking the myostatin gene have increased muscle mass. Thus, an inhibitor of myostatin may be useful therapeutically as an anabolic agent for muscle. However, since myostatin is expressed in both developing and adult muscles, it is not clear whether it regulates muscle mass during development or in adults. In order to test the hypothesis that myostatin regulates muscle mass in adults, we generated an inhibitory antibody to myostatin and administered it to adult mice. Here we show that mice treated pharmacologically with an antibody to myostatin have increased skeletal muscle mass and increased grip strength. These data show for the first time that myostatin acts postnatally as a negative regulator of skeletal muscle growth and suggest that myostatin inhibitors could provide a therapeutic benefit in diseases for which muscle mass is limiting.
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PMID:Inhibition of myostatin in adult mice increases skeletal muscle mass and strength. 1255 68

Activins and inhibins were first identified by virtue of their ability to regulate follicle-stimulating hormone (FSH) secretion from the anterior pituitary. Activins are also powerful regulators of gonadal functions. However, the physiological functions of activins are not restricted to reproductive tissues. Activins are involved in apoptosis of hepatocytes and B cells, fibrosis, inflammation and neurogenesis. Activins are regarded as novel drug targets since blocking activins would provide benefits by preventing apoptosis, fibrosis, inflammation and growth of several cancers. Activins are members of the transforming growth factor-beta (TGF-beta) family, which has numerous peptide growth and differentiation factors including activins, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs) and TGF-betas. Among them, GDF8 is also known as myostatin and is structurally related to activins. Myostatin is specifically expressed in the skeletal muscle lineage and is a candidate for muscle chalone negatively regulating the growth of myoblasts. Myostatin is regarded as a good drug target since therapeutics that modulate skeletal muscle growth would be useful for disease conditions such as muscular dystrophy, sarcopenia, cachexia and even diabetes. Recent studies have revealed that activins and myostatin signal through activin type II receptors (ActRIIA and ActRIIB) and their activities are regulated by extracellular binding proteins, follistatins and follistatin-related gene (FLRG). Furthermore, signaling of activins, myostatin and related ligands is also controlled by intracellular receptor-interacting proteins by novel mechanisms. In this review, I would like to show the current progress in the field emphasizing the importance of activins and myostatin as novel drug targets for immune, endocrine and metabolic disorders.
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PMID:Activins, myostatin and related TGF-beta family members as novel therapeutic targets for endocrine, metabolic and immune disorders. 1518 Apr 56

Insmed is developing mecasermin rinfabate, a recombinant complex of insulin-like growth factor-I (rhIGF-I) and binding protein-3 (rhIGFBP-3) [insulin-like growth factor-I/insulin-like growth factor binding protein-3, rhIGF-I/rhIGFBP-3, SomatoKine], for a number of metabolic and endocrine indications. In the human body, IGF-I circulates in the blood bound to a binding protein-3 (IGFBP-3), which regulates the delivery of IGF-I to target tissues, and particular proteases clip them apart in response to stresses and release IGF-I as needed. IGF-I, a naturally occurring hormone, is necessary for normal growth and metabolism. For the treatment of IGF-I deficiency, it is desirable to administer IGF-I bound to IGFBP-3 to maintain the normal equilibrium of these proteins in the blood. Mecasermin rinfabate (rhIGF-I/rhIGFBP-3) mimics the effects of the natural protein complex in the bloodstream and would augment the natural supply of these linked compounds. The most advanced indication in development of mecasermin rinfabate is the treatment of severe growth disorders due to growth hormone insensitivity syndrome (GHIS), also called Laron syndrome. GHIS is a genetic condition in which patients do not produce adequate quantities of IGF because of a failure to respond to the growth hormone signal. This results in a slower growth rate and short stature. Mecasermin rinfabate also has potential as replacement therapy for IGF-I, which may become depleted in indications such as major surgery, organ damage/failure, traumatic injury, cachexia and severe burn trauma. It also has potential for the treatment of osteoporosis. Mecasermin rinfabate was developed by Celtrix using its proprietary recombinant protein production technology. Subsequently, Celtrix was acquired by Insmed Pharmaceuticals on 1 June 2000. Insmed and Avecia of the UK have signed an agreement for manufacturing mecasermin rinfabate and its components, rhIGF-1 and rhIGFBP-3. CGMP clinical production of mecasermin rinfabate and its components will be carried out in Avecia's Advanced Biologics Centre, Billingham, UK, which manufactures recombinant-based medicines and vaccines at the capacity of up to 1000L. In April 2004, Insmed announced that it acquired a lease to operate the manufacturing facility formerly operated by Baxter for the commercial production of SomatoKine in Boulder, CO, USA. With the two manufacturing facilities for SomatoKine, Insmed plans to meet the development and commercial demands for the product over the next several years. In its 2003 Form-10K, Insmed announced plans to conduct comparative studies with the previously used drug substance and the new substance produced by Avecia. The comparative data will be included in the regulatory filing for mecasermin rinfabate. Mecasermin rinfabate was originally licensed to Welfide for Japan. On 1 October 2001, Welfide Corporation merged with Mitsubishi-Tokyo Pharmaceuticals to form Mitsubishi Pharma Corporation. The new company is a subsidiary of Mitsubishi Chemical. In October 2004, Insmed announced that Tzamal Pharma has been granted exclusive distribution and marketing rights for mecasermin rinfabate in certain Middle Eastern territories including Israel. Tzamal Pharma also acquired exclusive rights to Insmed's named patient programme for the agent in these territories. Tzamal Pharma intends to begin the appropriate registration activities for mecasermin rinfabate in the treatment of children with growth hormone-insensitivity syndrome. This pivotal, 12-month, multicentre, open-label trial in 30 children with GHIS was initiated in June 2003 and was designed to evaluate the safety and efficacy of the agent in prepubescent children with GHIS. The 6-month endpoint data analysis showed that mecasermin rinfabate given as a once-daily injection was safe and well tolerated. The agent demonstrated a significant increase in height velocity in children with GHIS similar to that observed by Pfizer in their pivotal study with twice-daily injections of rhIGF-I. The full results from the pivotal trial are expected in 2005. In April 2003 Insmed initiated a named patient programme in Europe that will make available mecasermin rinfabate for the treatment of GHIS-Laron syndrome. The treatment of patients was initiated in Scandinavia, with authorisation pending in several other European countries. Mecasermin rinfabate will be made available to those GHIS patients who, in the opinion of their doctor, may benefit from IGF-I therapy. At precommercial scale quantities, the drug will be available on a limited basis.A phase II dose-ranging study in children with GHIS was completed at Saint Bartholomew's and the Royal London School of Medicine, London, UK. A single dose of mecasermin rinfabate delivered the same amount of IGF-1 as two daily injections of unbound IGF-1. No adverse events were reported. Insmed has acquired an exclusive licence to Pharmacia's regulatory filings concerning yeast-derived insulin-like growth factor 1 (IGF-1). These filings were used by Pharmacia to receive marketing approvals in several European countries and also in the IND application with the US FDA. Insmed believes that this licence will facilitate the development of mecasermin rinfabate for the treatment of children with GHIS. In January 2003, Insmed announced positive results from a double-blind, placebo-controlled, dose-ranging study of mecasermin rinfabate in adolescent patients with type 1 diabetes receiving insulin therapy. The study was conducted at the University of Cambridge, Cambridge, UK, under supervision of Prof. D. Dunger. The researchers from The Robarts Research Institute and the University of Western Ontario, Canada (leading investigator T.L. Delovitch, the Sheldon H. Weinstein scientist in Diabetes at the University of Western Ontario) have found that mecasermin rinfabate complex was significantly more effective than IGF-1 in reducing the severity of insulitis, beta cell destruction and delaying the onset of type 1 diabetes. The study was supported by grants from Canadian Institutes of Health and the Juvenile Diabetes Research Foundation. Insmed plans to initiate large-scale phase II clinical studies in this indication. At the BIO 2004 Annual International Convention (BIO-2004) in June 2004, Insmed announced that it has received a grant from the US National Institutes of Health (NIH)/Muscular Dystrophy Association (MDA) worth USD $6.5 million to investigate the efficacy of mecasermin rinfabate for the treatment of myotonic dystrophy. It has also been granted orphan drug status for the treatment of GHIS-Laron syndrome in the US and Europe. In December 2003, Insmed announced that mecasermin rinfabate was designated orphan drug status by the FDA for the treatment of extreme insulin resistance. This provides Insmed with 7 years of market exclusivity following approval of mecasermin rinfabate for this indication. Insmed has received orphan drug designation for mecasermin rinfabate in the treatment of extreme insulin resistance in Europe (October 2004). In November 2004, Insmed was granted the European patent EP1183042 entitled "Methods for Treating Diabetes". This patent corresponds with the US patent US 6,040,292 also entitled "Methods for Treating Diabetes". Both patents cover type 1 and type 2 diabetes mellitus and insulin resistant diabetes including type A insulin resistance (the least severe form of extreme insulin resistance syndromes). In January 2004, Insmed obtained a non-exclusive licence to the patents for use of IGF-I for the treatment of extreme or severe insulin-resistant diabetes from Fujisawa Pharmaceutical. Insmed will have worldwide rights in territories (excluding Japan) with existing valid patent claims including the US and Europe. Insmed holds 28 US issued or allowed patents for the composition, production, antibodies and methods of use of mecasermin rinfabate. These US patents expire at various times between the years 2010 and 2019. Insmed through their lawyers filed its defense and counterclaim to the alleged patent infringement brought by Tercica against Insmed in the London High Court of Justice. Insmed asserted that it did not infringe any valid patent claims as none of the claims of the patent were patentable because the subject matter was not new. Insmed also stated that the patent did not involve an inventive step, did not have capability of industrial application and had no clear description of the invention so that invention can be performed by the person skilled in the art. Insmed is seeking revocation of the patent on these grounds.
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PMID:Mecasermin rinfabate: insulin-like growth factor-I/insulin-like growth factor binding protein-3, mecaserimin rinfibate, rhIGF-I/rhIGFBP-3. 1577 6

Cachexia contributes to nearly a third of all cancer deaths, yet the mechanisms underlying skeletal muscle wasting in this syndrome remain poorly defined. We report that tumor-induced alterations in the muscular dystrophy-associated dystrophin glycoprotein complex (DGC) represent a key early event in cachexia. Muscles from tumor-bearing mice exhibited membrane abnormalities accompanied by reduced levels of dystrophin and increased glycosylation on DGC proteins. Wasting was accentuated in tumor mdx mice lacking a DGC but spared in dystrophin transgenic mice that blocked induction of muscle E3 ubiquitin ligases. Furthermore, DGC deregulation correlated positively with cachexia in patients with gastrointestinal cancers. Based on these results, we propose that, similar to muscular dystrophy, DGC dysfunction plays a critical role in cancer-induced wasting.
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PMID:Dystrophin glycoprotein complex dysfunction: a regulatory link between muscular dystrophy and cancer cachexia. 1628 42

This review of androgen receptor (AR) coregulators, which also function as actin-binding proteins, intends to establish the connection between actin cytoskeletal components and androgen signaling, especially in skeletal muscle. In cellular and animal models, androgen activated AR modulates myoblasts proliferation, promotes sexual dimorphic muscle development, and alters muscle fiber type. In the clinical setting, administration of anabolic androgens can decrease cachexia and speed wound healing. During myogenesis and regeneration of skeletal muscle in embryo and adult, the membrane of myoblasts fuse and the actin cytoskeleton is rearranged to form an alignment with myosin to form myotubes then ultimately the myofibrils. Contraction of skeletal muscle promotes the growth of myocytes by coordinating signals from the neuromuscular junction to intra-myofibrils through costameres, the functional structure comprised of signal proteins closely associated with actin filaments and involved in muscular dystrophy. Therefore, the discovery of actin-binding proteins functioning as AR coregulators implies that androgen signaling is tightly regulated during the process of the development and regeneration of skeletal muscle. The search for selective androgen receptor modulators (SARM) that act precisely in skeletal muscle instead of other tissues could target the engineering of a SARM-AR complex that selectively recruits these coregulators.
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PMID:Actin associated proteins function as androgen receptor coregulators: an implication of androgen receptor's roles in skeletal muscle. 1859 Aug 22

In addition to gene correction therapy and cell transplantation techniques, multidisciplinary approaches to drug discovery and development offer promising therapeutic strategies for intractable genetic muscular disorders including muscular dystrophy. Inhibition of the production and activity of myostatin, a potent growth factor that determines skeletal muscle size, is a novel strategy for the treatment of muscle-wasting disorders such as muscular dystrophy, cachexia and sarcopenia. Myostatin blockers include myostatin-blocking antibodies, myostatin propeptide, follistatin and follistatin-related proteins, soluble myostatin receptors, small interfering RNA and small chemical inhibitors. This review describes the discovery and development of myostatin inhibitors.
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PMID:Targeting myostatin for therapies against muscle-wasting disorders. 1860 May 66

Loss of muscle mass can be the consequence of pathological changes, as observed in muscular dystrophies; or it can be secondary to cachexia-inducing diseases that cause muscle atrophy, such as cancer, heart disease, or chronic obstructive pulmonary disease; or it can be a consequence of aging or simple disuse. Although muscular dystrophies are rare, muscle loss affects millions of people worldwide. We discuss the molecular mechanisms involved in muscular dystrophy and in muscle atrophy and present current strategies aimed at ameliorating these diseases. Finally, we discuss whether lessons learned from studying muscular dystrophies will also be helpful for halting muscle loss secondary to nondystrophic diseases and whether strategies to halt muscle atrophy have potential for the treatment of muscular dystrophies.
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PMID:Molecular mechanisms and treatment options for muscle wasting diseases. 2093 44

The extraocular muscles (EOM) are spared from pathology in aging and many forms of muscular dystrophy. Despite many studies, this sparing remains an enigma. The EOM have a distinct embryonic lineage compared to somite-derived muscles, and we have shown that they continuously remodel throughout life, maintaining a population of activated satellite cells even in aging. These data suggested the hypothesis that there is a population of myogenic precursor cells (mpcs) in EOM that is different from those in limb, with either elevated numbers of stem cells and/or mpcs with superior proliferative capacity compared to mpcs in limb. Using flow cytometry, EOM and limb muscle mononuclear cells were compared, and a number of differences were seen. Using two different cell isolation methods, EOM have significantly more mpcs per mg muscle than limb skeletal muscle. One specific subpopulation significantly increased in EOM compared to limb was positive for CD34 and negative for Sca-1, M-cadherin, CD31, and CD45. We named these the EOMCD34 cells. Similar percentages of EOMCD34 cells were present in both newborn EOM and limb muscle. They were retained in aged EOM, whereas the population decreased significantly in adult limb muscle and were extremely scarce in aged limb muscle. Most importantly, the percentage of EOMCD34 cells was elevated in the EOM from both the mdx and the mdx/utrophin(-/-) (DKO) mouse models of DMD and extremely scarce in the limb muscles of these mice. In vitro, the EOMCD34 cells had myogenic potential, forming myotubes in differentiation media. After determining a media better able to induce proliferation in these cells, a fusion index was calculated. The cells isolated from EOM had a 40% higher fusion index compared to the same cells isolated from limb muscle. The EOMCD34 cells were resistant to both oxidative stress and mechanical injury. These data support our hypothesis that the EOM may be spared in aging and in muscular dystrophies due to a subpopulation of mpcs, the EOMCD34 cells, that are retained in significantly higher percentages in normal, mdx and DKO mice EOM, appear to be resistant to elevated levels of oxidative stress and toxins, and actively proliferate throughout life. Current studies are focused on further defining the EOMCD34 cell subtype molecularly, with the hopes that this may shed light on a cell type with potential therapeutic use in patients with sarcopenia, cachexia, or muscular dystrophy.
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PMID:Sparing of extraocular muscle in aging and muscular dystrophies: a myogenic precursor cell hypothesis. 2127


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