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