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Exercise effects in Huntington disease

English title Exercise effects in Huntington disease
Applicant Jung Hans Heinrich
Number 135539
Funding scheme Project funding (Div. I-III)
Research institution Neurologische Klinik Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Neurology, Psychiatry
Start/End 01.10.2011 - 31.12.2014
Approved amount 375'000.00
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All Disciplines (3)

Discipline
Neurology, Psychiatry
Physiology : other topics
Pathophysiology

Keywords (5)

Huntington disease; chorea syndrome; muscle; exercise; respiratory chain function

Lay Summary (English)

Lead
Lay summary

Huntington disease (HD) is an incurable and fatal disorder that affectsdementia decline and cognitive muscle function and leads to . HD was long considered a brain disorder but meanwhile it was shown that HD also affects other tissues such as muscle, leading to muscle wasting. Previous studies suggested that the muscle disorder might be caused by an impaired energy metabolism through mitochondrial dysfunction, which also might also contribute to brain pathology.

In muscle tissue of healthy persons, a protein named PGC 1- a seems to regulate many, if not all of the adaptations of muscle metabolism and mitochondrial biogenesis to chronic endurance training. It was shown that PGC 1- a is reduced in muscle tissue of human HD patients and animal models of HD.

We aim investigating whether endurance exercise has the capability of stabilizing and / or reversing PGC-1a dependent decline of muscle function and structure in HD patients, and whether muscle training ameliorates muscular and cardiovascular function, as well as coordination and cognitive decline in HD. To this end, we will train 20 male HD patients using a 6 months progressive endurance exercise program. In order to compare the size effect of exercise between HD patients and healthy individuals, 20 age-matched healthy males will perform the identical exercise regimen as HD patients.  Before and after the training period, we will assess metabolic and functional data. In addition, we will analyze muscle tissue samples for muscle fiber structure, metabolic phenotype and cellular pathology. Finally, gene and protein expression analyses will be performed on muscle tissue extracts to gain insights into the molecular regulation of training adaptations in HD.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Effects of endurance training on skeletal muscle mitochondrial function in Huntington disease patients
Mueller Sandro Manuel, Gehrig Saskia Maria, Petersen Jens A., Frese Sebastian, Mihaylova Violeta, Ligon-Auer Maria, Khmara Natalia, Nuoffer Jean-Marc, Schaller André, Lundby Carsten, Toigo Marco, Jung Hans H. (2017), Effects of endurance training on skeletal muscle mitochondrial function in Huntington disease patients, in Orphanet Journal of Rare Diseases, 12(1), 184-184.
Skeletal muscle characteristics and mitochondrial function in Huntington's disease patientsSkeletal Muscle in Huntington's Disease
Gehrig Saskia Maria, Petersen Jens A., Frese Sebastian, Mueller Sandro Manuel, Mihaylova Violeta, Ligon-Auer Maria, Lundby Carsten, Toigo Marco, Jung Hans H. (2017), Skeletal muscle characteristics and mitochondrial function in Huntington's disease patientsSkeletal Muscle in Huntington's Disease, in Movement Disorders, 32(8), 1258-1259.
Exercise effects in Huntington disease
Frese Sebastian, Petersen Jens A., Ligon-Auer Maria, Mueller Sandro Manuel, Mihaylova Violeta, Gehrig Saskia M., Kana Veronika, Rushing Elisabeth J., Unterburger Evelyn, Kägi Georg, Burgunder Jean-Marc, Toigo Marco, Jung Hans H. (2017), Exercise effects in Huntington disease, in Journal of Neurology, 264(1), 32-39.

Collaboration

Group / person Country
Types of collaboration
PD Dr. G. Kägi, Klinik für Neurologie, Kantonsspital St. Gallen Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
PD Dr. J.M. Nuoffer, Institut für Klinische Chemie, Universitätsspital Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Dr. C. Lundby, Institute of Physiology, University of Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
- Exchange of personnel
Prof. Dr. J.-M. Burgunder, Neurologische Klinik, Universitätsspital Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. A. Schaller, Institut für Medizinische Genetik, Universitätsspital Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
4th Swiss Movement Disorders Symposium Talk given at a conference Exercise Effects in Huntington Disease 30.08.2012 Luzern, Switzerland Frese Sebastian; Petersen Jens; Jung Hans Heinrich;


Communication with the public

Communication Title Media Place Year
Media relations: radio, television Gesundheit heute: Chorea Huntington SRF 1 German-speaking Switzerland 2014

Abstract

Huntington’s disease (HD) is an incurable and fatal disorder characterised by progressive neurodegeneration of the basal ganglia and, in later disease stages, the cerebral cortex. HD is caused by an expansion of a glutamine-encoding CAG-repeat in the Huntingtin gene which encodes a protein of a hitherto not fully elucidated physiological function. Contrary to earlier thinking, HD is associated with abnormalities in peripheral tissues which might even contribute to brain pathology. Among the hallmarks of HD is skeletal muscle wasting, despite the muscles being highly active as a result of hyperkinesia. Studies on cultured skeletal muscle cells from patients with HD revealed several mitochondrial abnormalities, including respiratory-chain dysfunction, morphologically abnormal christae, cytochrome c release, and apoptosis. In line with these findings, in vivo human magnetic resonance imaging studies demonstrated impaired energy metabolism. Based on these data, there is converging evidence that muscle tissue is affected in HD.Mitochondrial impairment and muscle atrophy in human HD patients and murine models of HD are associated with altered expression of peroxisome-proliferator-activated receptor- ? (PPAR-?) co-activator 1a (PGC-1a), a transcriptional cofactor that regulates several metabolic processes, including mitochondrial biogenesis and oxidative phosphorylation. PGC-1a is known to prevent protein catabolism and muscle wasting in a variety of contexts. Furthermore, it seems to regulate many, if not all of the adaptations of muscle fibres to chronic endurance training, and induces improved exercise performance and increased peak oxygen uptake. Current evidence suggests that:- PGC-1a mRNA is reduced in muscles of both HD patients and HD mice.- Diminished expression of PGC-1a in HD mice correlates with the occurrence of both muscle fibre atrophy and mitochondrial dysfunction. - Treatment with pharmaceutical agents or exercise to activate PGC-1a could exert therapeutic benefits.Since in healthy humans it has been shown that basal PGC-1a expression is elevated after chronic endurance exercise, we aim at investigating whether endurance exercise has the capability of stabilizing and / or reversing PGC-1a dependent alterations of muscle function and structure in HD patients, and whether muscle training ameliorates musculoskeletal and cardiovascular function, as well as motor and cognitive symptoms in HD patients. Twenty male HD patients and the corresponding number of age-matched healthy males will participate in this study. The HD patients will monitored for 6 months to evaluate the natural course of the disorder followed by 6 months of progressive endurance exercise. In order to compare the size effect of exercise between healthy and HD participants, 20 healthy males will perform the identical exercise regimen as HD patients. Before the observation period in HD patients as well as immediately before and after the training in HD patients and controls, clinical, metabolic and functional data will be obtained, and minimally invasive muscle needle biopsies for histological, biochemical and gene expression analyses will be performed. In HD patients, endurance training is expected to ameliorate or reverse the HD-associated changes in muscle properties, and eventually stabilize or ameliorate the course of concurrent cerebral HD symptoms.
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