Exercise Effects in Huntington's Disease

Huntington's disease (HD) is an incurable and fatal disorder characterised by progressive degeneration of the basal ganglia and the cerebral cortex. Contrary to earlier thinking, HD is associated with abnormalities in peripheral tissues which might even contribute to brain pathology including muscle wasting, mitochondrial abnormalities, and impaired muscle energy metabolism. Mitochondrial impairment and muscle atrophy in human HD patients and murine models of HD are associated with altered expression of PGC-1a, a transcriptional cofactor that 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. 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.

Study Overview

• Status: Completed
• Conditions: Huntington's Disease
• Intervention / Treatment: Behavioral: Exercise training

Detailed Description

Huntington disease (HD) is an incurable and fatal disorder that affects muscle function and leads to cognitive decline and dementia. 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- α 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- α 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-1α 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. Within one week before the training period starts and within one week after it has ended, 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.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Switzerland
  • ZH
    • Zurich, ZH, Switzerland, 8091
      • University Hospital Zurich, Division of Neurology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion criteria: Inclusion criteria for HD subjects are:

• Male gender
• Genetically verified diagnosis of HD
• Age 30 to 50 years
• Presence of only mild to moderate neurological, cognitive or muscular impairment allowing the subjects to give their written informed consent and to participate in the endurance training (UHDRS 30 or lower)

For healthy control participants, inclusion criteria are:

• male gender 9
• age 30 to 50 years
• absence of physical or mental illness

Exclusion criteria: Exclusion criteria for HD subjects are:

• Female gender
• Advanced neurological, cognitive or muscular impairment related to HD that does not allow patients to participate in the endurance training and/or to give their written informed consent
• Cardiovascular disease or any other medical condition that might not be compatible with endurance training
• CK levels > 300 U/L

Exclusion criteria for healthy control participants are:

• cardiovascular disease
• any other medical condition that might not be compatible with endurance training
• CK levels > 300 U/L.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Exercise Training: HD subjects; Endurance exercise for 6 months (30 min per week) starting one week after a 6-months natural course observation	Behavioral: Exercise training; 6 months of exercise training (2 times 30 min per week) starting one week after a 6-months natural course observation period
Other: Exercise Training: healthy subjects; 6 months of exercise training (2 times 30 min per week)	Behavioral: Exercise training; 6 months of exercise training (2 times 30 min per week) starting one week after a 6-months natural course observation period

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in Unified Huntington's Disease Rating Scale (UHDRS)	Baseline and 6 months

Collaborators and Investigators

• Sponsor: University of Zurich
• Investigators: Principal Investigator: Hans H Jung, Professor MD, University Hospital Zurich, Division of Neurology

Publications and helpful links

General Publications

• Mueller SM, Gehrig SM, Petersen JA, Frese S, Mihaylova V, Ligon-Auer M, Khmara N, Nuoffer JM, Schaller A, Lundby C, Toigo M, Jung HH. Effects of endurance training on skeletal muscle mitochondrial function in Huntington disease patients. Orphanet J Rare Dis. 2017 Dec 19;12(1):184. doi: 10.1186/s13023-017-0740-z.

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (Actual): January 1, 2018
• Study Completion (Actual): January 1, 2018

Study Registration Dates

• First Submitted: May 24, 2012
• First Submitted That Met QC Criteria: June 12, 2013
• First Posted (Estimate): June 17, 2013

Study Record Updates

• Last Update Posted (Actual): June 13, 2018
• Last Update Submitted That Met QC Criteria: June 11, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Genetic Diseases, Inborn; Basal Ganglia Diseases; Movement Disorders; Neurodegenerative Diseases; Dyskinesias; Heredodegenerative Disorders, Nervous System; Dementia; Cognition Disorders; Chorea; Huntington Disease
• Other Study ID Numbers: KEK-ZH-Nr. 2009-0119