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      Skeletal muscle pathology in Huntington's disease

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          Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by the expansion of a polyglutamine stretch within the huntingtin protein (HTT). The neurological symptoms, that involve motor, cognitive and psychiatric disturbances, are caused by neurodegeneration that is particularly widespread in the basal ganglia and cereberal cortex. HTT is ubiquitously expressed and in recent years it has become apparent that HD patients experience a wide array of peripheral organ dysfunction including severe metabolic phenotype, weight loss, HD-related cardiomyopathy and skeletal muscle wasting. Although skeletal muscles pathology became a hallmark of HD, the mechanisms underlying muscular atrophy in this disorder are unknown. Skeletal muscles account for approximately 40% of body mass and are highly adaptive to physiological and pathological conditions that may result in muscle hypertrophy (due to increased mechanical load) or atrophy (inactivity, chronic disease states). The atrophy is caused by degeneration of myofibers and their replacement by fibrotic tissue is the major pathological feature in many genetic muscle disorders. Under normal physiological conditions the muscle function is orchestrated by a network of intrinsic hypertrophic and atrophic signals linked to the functional properties of the motor units that are likely to be imbalanced in HD. In this article, we highlight the emerging field of research with particular focus on the recent studies of the skeletal muscle pathology and the identification of new disease-modifying treatments.

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          Most cited references 48

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          A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group.

           M Shah,  N Datson,  L Srinidhi (1993)
          The Huntington's disease (HD) gene has been mapped in 4p16.3 but has eluded identification. We have used haplotype analysis of linkage disequilibrium to spotlight a small segment of 4p16.3 as the likely location of the defect. A new gene, IT15, isolated using cloned trapped exons from the target area contains a polymorphic trinucleotide repeat that is expanded and unstable on HD chromosomes. A (CAG)n repeat longer than the normal range was observed on HD chromosomes from all 75 disease families examined, comprising a variety of ethnic backgrounds and 4p16.3 haplotypes. The (CAG)n repeat appears to be located within the coding sequence of a predicted approximately 348 kd protein that is widely expressed but unrelated to any known gene. Thus, the HD mutation involves an unstable DNA segment, similar to those described in fragile X syndrome, spino-bulbar muscular atrophy, and myotonic dystrophy, acting in the context of a novel 4p16.3 gene to produce a dominant phenotype.
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            Metabolic control through the PGC-1 family of transcription coactivators.

            Many complex biological programs are controlled at the level of gene transcription by DNA binding transcription factors. Recent studies have revealed a novel mode of regulation by coactivator proteins, best illustrated by the PGC-1 family of coactivators. These factors are highly responsive to a variety of environmental cues, from temperature to nutritional status to physical activity, and they coordinately regulate metabolic pathways and biological processes in a tissue-specific manner. Notably, the PGC-1 coactivators play a critical role in the maintenance of glucose, lipid, and energy homeostasis and are likely involved in the pathogenic conditions such as obesity, diabetes, neurodegeneration, and cardiomyopathy. These actions also raise new opportunities for the development of novel therapeutics.
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              Huntington's disease.

              Huntington's disease is an autosomal-dominant, progressive neurodegenerative disorder with a distinct phenotype, including chorea and dystonia, incoordination, cognitive decline, and behavioural difficulties. Typically, onset of symptoms is in middle-age after affected individuals have had children, but the disorder can manifest at any time between infancy and senescence. The mutant protein in Huntington's disease--huntingtin--results from an expanded CAG repeat leading to a polyglutamine strand of variable length at the N-terminus. Evidence suggests that this tail confers a toxic gain of function. The precise pathophysiological mechanisms of Huntington's disease are poorly understood, but research in transgenic animal models of the disorder is providing insight into causative factors and potential treatments.

                Author and article information

                1Department of Social Medicine, Poznan University of Medical Sciences Poznan, Poland
                2MRC National Institute for Medical Research London, UK
                3Department of Medical and Molecular Genetics, King's College London London, UK
                Author notes

                Edited by: Julio L. Vergara, University of California, Los Angeles, USA

                Reviewed by: Seth L. Robia, Loyola University Chicago, USA; Andrew Alvin Voss, Wright State University, USA

                *Correspondence: Daniel Zielonka, Department of Social Medicine, Poznan University of Medical Sciences, Rokietnicka Str., No. 5 “C,” 60-806 Poznan, Poland e-mail: daniel.zielonka@ ;
                Michal Mielcarek, Department of Medical and Molecular Genetics, School of Medicine, King's College London, 8th Floor Tower Wing, Guy's Hospital Great Maze Pond, London, SE1 9RT, UK e-mail: michal.mielcarek@

                This article was submitted to Striated Muscle Physiology, a section of the journal Frontiers in Physiology.

                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                06 October 2014
                : 5
                4186279 10.3389/fphys.2014.00380
                Copyright © 2014 Zielonka, Piotrowska, Marcinkowski and Mielcarek.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Figures: 1, Tables: 1, Equations: 0, References: 49, Pages: 6, Words: 4451
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