Rehabilitative Impact of Exercise Training on Human Skeletal Muscle Transcriptional Programs in Parkinson’s Disease

We conducted, in persons with Parkinson's disease (PD), a thorough assessment of neuromotor function and performance in conjunction with phenotypic analyses of skeletal muscle tissue, and further tested the adaptability of PD muscle to high-intensity exercise training. Fifteen participants with PD (Hoehn and Yahr stage 2–3) completed 16 wk of high-intensity exercise training designed to simultaneously challenge strength, power, endurance, balance, and mobility function. Skeletal muscle adaptations ( P < 0.05) to exercise training in PD included myofiber hypertrophy (type I: +14%, type II: +36%), shift to less fatigable myofiber type profile, and increased mitochondrial complex activity in both subsarcolemmal and intermyofibrillar fractions (I: +45–56%, IV: +39–54%). These adaptations were accompanied by a host of functional and clinical improvements ( P < 0.05): total body strength (+30–56%); leg power (+42%); single leg balance (+34%); sit-to-stand motor unit activation requirement (−30%); 6-min walk (+43 m), Parkinson's Disease Quality of Life Scale (PDQ-39, −7.8pts); Unified Parkinson's Disease Rating Scale (UPDRS) total (−5.7 pts) and motor (−2.7 pts); and fatigue severity (−17%). Additionally, PD subjects in the pretraining state were compared with a group of matched, non-PD controls (CON; did not exercise). A combined assessment of muscle tissue phenotype and neuromuscular function revealed a higher distribution and larger cross-sectional area of type I myofibers and greater type II myofiber size heterogeneity in PD vs. CON ( P < 0.05). In conclusion, persons with moderately advanced PD adapt to high-intensity exercise training with favorable changes in skeletal muscle at the cellular and subcellular levels that are associated with improvements in motor function, physical capacity, and fatigue perception.

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Effect of Multimodal Exercise Training on Walking Economy in Individuals With Parkinson's Disease

Case Medical Research ◽

10.31525/ct1-nct03864393 ◽

2019 ◽

Author(s):

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Exercise Training ◽

Walking Economy

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Transcriptional regulation of gene expression in human skeletal muscle during recovery from exercise

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2000.279.4.e806 ◽

2000 ◽

Vol 279 (4) ◽

pp. E806-E814 ◽

Cited By ~ 351

Author(s):

Henriette Pilegaard ◽

George A. Ordway ◽

Bengt Saltin ◽

P. Darrell Neufer

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Human Skeletal Muscle ◽

Molecular Mechanisms ◽

Uncoupling Protein ◽

Pyruvate Dehydrogenase Kinase ◽

Heme Oxygenase 1 ◽

Metabolic Efficiency ◽

Vastus Lateralis Muscle ◽

Mrna Levels

Exercise training elicits a number of adaptive changes in skeletal muscle that result in an improved metabolic efficiency. The molecular mechanisms mediating the cellular adaptations to exercise training in human skeletal muscle are unknown. To test the hypothesis that recovery from exercise is associated with transcriptional activation of specific genes, six untrained male subjects completed 60–90 min of exhaustive one-legged knee extensor exercise for five consecutive days. On day 5, nuclei were isolated from biopsies of the vastus lateralis muscle of the untrained and the trained leg before exercise and from the trained leg immediately after exercise and after 15 min, 1 h, 2 h, and 4 h of recovery. Transcriptional activity of the uncoupling protein 3 (UCP3), pyruvate dehydrogenase kinase 4 (PDK4), and heme oxygenase-1 (HO-1) genes (relative to β-actin) increased by three- to sevenfold in response to exercise, peaking after 1–2 h of recovery. Increases in mRNA levels followed changes in transcription, peaking between 2 and 4 h after exercise. Lipoprotein lipase and carnitine pamitoyltransferase I gene transcription and mRNA levels showed similar but less dramatic induction patterns, with increases ranging from two- to threefold. In a separate study, a single 4-h bout of cycling exercise ( n = 4) elicited from 5 to >20-fold increases in UCP3, PDK4, and HO-1 transcription, suggesting that activation of these genes may be related to the duration or intensity of exercise. These data demonstrate that exercise induces transient increases in transcription of metabolic genes in human skeletal muscle. Moreover, the findings suggest that the cumulative effects of transient increases in transcription during recovery from consecutive bouts of exercise may represent the underlying kinetic basis for the cellular adaptations associated with exercise training.

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Exercise training increases branched-chain oxoacid dehydrogenase kinase content in human skeletal muscle

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00115.2007 ◽

2007 ◽

Vol 293 (3) ◽

pp. R1335-R1341 ◽

Cited By ~ 18

Author(s):

Krista R. Howarth ◽

Kirsten A. Burgomaster ◽

Stuart M. Phillips ◽

Martin J. Gibala

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Protein Content ◽

Human Skeletal Muscle ◽

Acute Exercise ◽

Citrate Synthase ◽

Muscle Protein ◽

Moderate Intensity ◽

Main Effect ◽

Branched Chain

The branched-chain oxoacid dehydrogenase complex (BCOAD) is rate determining for the oxidation of branched-chain amino acids (BCAAs) in skeletal muscle. Exercise training blunts the acute exercise-induced activation of BCOAD (BCOADa) in human skeletal muscle (McKenzie S, Phillips SM, Carter SL, Lowther S, Gibala MJ, Tarnopolsky MA. Am J Physiol Endocrinol Metab 278: E580–E587, 2000); however, the mechanism is unknown. We hypothesized that training would increase the muscle protein content of BCOAD kinase, the enzyme responsible for inactivation of BCOAD by phosphorylation. Twenty subjects [23 ± 1 yr; peak oxygen uptake (V̇o2peak) = 41 ± 2 ml·kg−1·min−1] performed 6 wk of either high-intensity interval or continuous moderate-intensity training on a cycle ergometer ( n = 10/group). Before and after training, subjects performed 60 min of cycling at 65% of pretraining V̇o2peak, and needle biopsy samples (vastus lateralis) were obtained before and immediately after exercise. The effect of training was demonstrated by an increased V̇o2peak, increased citrate synthase maximal activity, and reduced muscle glycogenolysis during exercise, with no difference between groups (main effects, P < 0.05). BCOADa was lower after training (main effect, P < 0.05), and this was associated with a ∼30% increase in BCOAD kinase protein content (main effect, P < 0.05). We conclude that the increased protein content of BCOAD kinase may be involved in the mechanism for reduced BCOADa after exercise training in human skeletal muscle. These data also highlight differences in models used to study the regulation of skeletal muscle BCAA metabolism, since exercise training was previously reported to increase BCOADa during exercise and decrease BCOAD kinase content in rats (Fujii H, Shimomura Y, Murakami T, Nakai N, Sato T, Suzuki M, Harris RA. Biochem Mol Biol Int 44: 1211–1216, 1998).

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Skeletal muscle adaptations to exercise are not influenced by metformin treatment in humans: secondary analyses of two randomised, clinical trials.

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2021-0194 ◽

2021 ◽

Author(s):

Nanna Skytt Pilmark ◽

Laura Oberholzer ◽

Jens Frey Halling ◽

Jonas M. Kristensen ◽

Christina Pedersen Bønding ◽

...

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Exercise Training ◽

Human Skeletal Muscle ◽

Acute Exercise ◽

Metformin Treatment ◽

Ampk Activation ◽

Double Blind ◽

Parallel Group ◽

Exercise Induced

Metformin and exercise both improve glycemic control, but in vitro studies have indicated that an interaction between metformin and exercise occurs in skeletal muscle, suggesting a blunting effect of metformin on exercise training adaptations. Two studies (a double-blind, parallel-group, randomized clinical trial conducted in 29 glucose-intolerant individuals and a double-blind, cross-over trial conducted in 15 healthy lean males) were included in this paper. In both studies, the effect of acute exercise +/- metformin treatment on different skeletal muscle variables, previously suggested to be involved in a pharmaco-physiological interaction between metformin and exercise, was assessed. Furthermore, in the parallel-group trial, the effect of 12 weeks of exercise training was assessed. Skeletal muscle biopsies were obtained before and after acute exercise and 12 weeks of exercise training, and mitochondrial respiration, oxidative stress and AMPK activation was determined. Metformin did not significantly affect the effects of acute exercise or exercise training on mitochondrial respiration, oxidative stress or AMPK activation, indicating that the response to acute exercise and exercise training adaptations in skeletal muscle is not affected by metformin treatment. Further studies are needed to investigate whether an interaction between metformin and exercise is present in other tissues, e.g. the gut. Trial registration: ClinicalTrials.gov (NCT03316690 and NCT02951260). Novelty bullets • Metformin does not affect exercise-induced alterations in mitochondrial respiratory capacity in human skeletal muscle • Metformin does not affect exercise-induced alterations in systemic levels of oxidative stress nor emission of reactive oxygen species from human skeletal muscle • Metformin does not affect exercise-induced AMPK activation in human skeletal muscle

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Exercise training remodels human skeletal muscle mitochondrial fission and fusion machinery towards a pro‐elongation phenotype

Acta Physiologica ◽

10.1111/apha.13216 ◽

2018 ◽

Vol 225 (4) ◽

pp. e13216 ◽

Cited By ~ 20

Author(s):

Christopher L. Axelrod ◽

Ciarán E. Fealy ◽

Anny Mulya ◽

John P. Kirwan

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Human Skeletal Muscle ◽

Mitochondrial Fission

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Regulation of autophagy in human skeletal muscle: effects of exercise, exercise training and insulin stimulation

The Journal of Physiology ◽

10.1113/jp271405 ◽

2016 ◽

Vol 594 (3) ◽

pp. 745-761 ◽

Cited By ~ 47

Author(s):

Andreas M. Fritzen ◽

Agnete B. Madsen ◽

Maximilian Kleinert ◽

Jonas T. Treebak ◽

Anne-Marie Lundsgaard ◽

...

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Human Skeletal Muscle ◽

Insulin Stimulation

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Inflammation And Denervation In Skeletal Muscle Of Parkinson’S Disease Patients

Medicine & Science in Sports & Exercise ◽

10.1249/01.mss.0000535420.76238.d0 ◽

2018 ◽

Vol 50 (5S) ◽

pp. 103

Author(s):

Kaleen Lavin ◽

Neil Kelly ◽

Kelley Hammond ◽

Irina Isakova-Donahue ◽

Marcas Bamman

Keyword(s):

Skeletal Muscle ◽

Parkinson’S Disease ◽

Parkinson's Disease

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Fatigability and Cardiorespiratory Impairments in Parkinson’s Disease: Potential Non-Motor Barriers to Activity Performance

Journal of Functional Morphology and Kinesiology ◽

10.3390/jfmk5040078 ◽

2020 ◽

Vol 5 (4) ◽

pp. 78

Author(s):

Andrew E. Pechstein ◽

Jared M. Gollie ◽

Andrew A. Guccione

Keyword(s):

Skeletal Muscle ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cardiorespiratory Fitness ◽

Oxygen Delivery ◽

Disease Diagnosis ◽

Rate Of Change ◽

Motor Symptom ◽

Biological Aging ◽

Over Time

Parkinson’s disease (PD) is the second most common neurodegenerative condition after Alzheimer’s disease, affecting an estimated 160 per 100,000 people 65 years of age or older. Fatigue is a debilitating non-motor symptom frequently reported in PD, often manifesting prior to disease diagnosis, persisting over time, and negatively affecting quality of life. Fatigability, on the other hand, is distinct from fatigue and describes the magnitude or rate of change over time in the performance of activity (i.e., performance fatigability) and sensations regulating the integrity of the performer (i.e., perceived fatigability). While fatigability has been relatively understudied in PD as compared to fatigue, it has been hypothesized that the presence of elevated levels of fatigability in PD results from the interactions of homeostatic, psychological, and central factors. Evidence from exercise studies supports the premise that greater disturbances in metabolic homeostasis may underly elevated levels of fatigability in people with PD when engaging in physical activity. Cardiorespiratory impairments constraining oxygen delivery and utilization may contribute to the metabolic alterations and excessive fatigability experienced in individuals with PD. Cardiorespiratory fitness is often reduced in people with PD, likely due to the combined effects of biological aging and impairments specific to the disease. Decreases in oxygen delivery (e.g., reduced cardiac output and impaired blood pressure responses) and oxygen utilization (e.g., reduced skeletal muscle oxidative capacity) compromise skeletal muscle respiration, forcing increased reliance on anaerobic metabolism. Thus, the assessment of fatigability in people with PD may provide valuable information regarding the functional status of people with PD not obtained with measures of fatigue. Moreover, interventions that target cardiorespiratory fitness may improve fatigability, movement performance, and health outcomes in this patient population.

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