Juan Carlos Magaña, Cláudia Maria Deus, Laura Baldellou, Merce Avellanet, Elvira Gea-Rodríguez, Silvia Enriquez-Calzada, Ariadna Laguna, Marta Martínez-Vicente, Jorge Hernández-Vara, Maria Giné-Garriga, Susana Patricia Pereira, Joel Montane
Abstract
Parkinson’s disease (PD) is characterized by the progressive dopaminergic neuron degeneration, resulting in striatal dopamine deficiency. Mitochondrial dysfunction and oxidative stress are associated with PD pathogenesis. Physical activity (PA) has been shown to ameliorate neurological impairments and to impede age-related neuronal loss. In addition, skin fibroblasts have been identified as surrogate indicators of pathogenic processes correlating with clinical measures. The PARKEX study aims to compare the effects of two different PA programs, analyzing the impact on mitochondrial function in patients’ skin fibroblasts as biomarkers for disease status and metabolic improvement. Early-stage PD patients (n = 24, H&Y stage I to III) will be randomized into three age- and sex-matched groups. Group 1 (n = 8) will undergo basic physical training (BPT) emphasizing strength and resistance. Group 2 (n = 8) will undergo BPT combined with functional exercises (BPTFE), targeting the sensorimotor pathways that are most affected in PD (proprioception-balance-coordination) together with cognitive and motor training (Dual task training). Group 3 (n = 8) will serve as control (sedentary group; Sed). Participants will perform three sessions per week for 12 weeks. Assessment of motor function, quality of life, sleep quality, cognitive aspects and humor will be conducted pre- and post-intervention.
Introduction
Parkinson’s disease (PD) is a disorder characterized by the progressive degeneration of dopaminergic neurons resulting in a deficiency of dopamine in the striatum in the basal ganglia [1]. PD patients experience both motor and non-motor symptoms, including anxiety, depression, sleep and gastrointestinal alterations, among others. The motor symptoms typically manifest gradually, initially asymmetrical and later bilateral. The most common primary motor symptoms include akinesia (lack of spontaneous voluntary movement), bradykinesia (slowness of movement), resting tremor (hands, arms, legs, jaw, and face), rigidity (arms, legs, and trunk), and postural instability. Additionally, people with PD may experience difficulties with balance and coordination [2]. Although the exact mechanism behind the neurodegeneration of dopaminergic cells remains uncertain, current understanding suggests an interaction between genetic and environmental factors as contributors [3,4].
Methods and analysis
Study design
PARKEX trial is a randomized clinical trial with an open design (registered at clinicaltrials.gov; NCT05963425). It is a non-pharmacologically interventional study, with a total of twenty-four patients. Screening and assessment visits are occurring in both neurology and PA laboratory settings.
A SPIRIT schedule and overview of the study design can be found in Figs 1 and 2.
This protocol has been developed following the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist (see S1 Fig) [29].
Subject recruitment
Participants for the study will be recruited by the Grup de Malalties Neurodegeneratives of the Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. To ensure the minimum required sample size of 24 patients, as stipulated in the project, the VHIR researchers will leverage their connections with the Catalan Parkinson’s Association and other Movement Disorders Units in prominent hospitals across the state.
Discussion
Accumulating evidence supports the potential benefits of PA for patients with PD, including both general health improvements and disease-specific effects. However, the exact mechanism connecting skeletal muscle-increased activity and mitochondrial remodeling in PD are poorly elucidated. The PARKEX study is the first clinical trial that aims to evaluate the effects of two PA programs on skin fibroblasts mitochondrial function from patients with PD, as well as their impact on motor function, quality of life, sleep, cognitive and mood aspects. The 12-week implementation of the BPT and BPTFE programs is expected to positively impact relevant clinical aspects of PD by enhancing systemic mitochondrial function, restoring mitochondrial metabolism, and influencing gene expression patterns. These improvements are anticipated to translate into potential neuroprotective effects. Additionally, the PARKEX clinical trial will provide insights into the degree of mitochondrial function improvements in PD through a comparative analysis of BPT and BPTFE programs and aims to unveil, for the first time, the biochemically-detectable changes in skin fibroblasts from PD patients that reflect the metabolic and mitochondrial benefits of PA. This crucial observation will demonstrate the tangible and measurable effects of PA on mitochondrial function at the cellular level. Understanding the regulation of the mitochondrial function by PA in PD holds significant promise in defining interventions to delay disease onset and developing new therapeutic approaches not only for PD but also for other neurodegenerative disorders.
Acknowledgments
The authors would like to thank all PD patients who will contribute to the performance of the study and the Associació Catalana per al Parkinson for their invaluable help in diffusion of the study and the subject recruitment.
Citation: Magaña JC, Deus CM, Baldellou L, Avellanet M, Gea-Rodríguez E, Enriquez-Calzada S, et al. (2023) Investigating the impact of physical activity on mitochondrial function in Parkinson’s disease (PARKEX): Study protocol for A randomized controlled clinical trial. PLoS ONE 18(11): e0293774. https://doi.org/10.1371/journal.pone.0293774
Editor: Vanessa Carels, PLoS ONE, UNITED STATES
Received: October 18, 2023; Accepted: October 23, 2023; Published: November 22, 2023
Copyright: © 2023 Magaña et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: No datasets were generated or analysed during the current study. All relevant data from this study will be made available upon study completion.
Funding: This work was supported by research funds provided by the Ajuts a l’Activitat de Recerca del Personal Docent i Investigador de la Universitat Ramon Llull (2021-URL-Proj-004 and 2023-URL-Proj-016), the Funding program PGRiD 2019–2021 of the Faculty of Psychology, Education, and Sport Sciences (APR-FPCEE2122/04) and by the European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme under project CENTRO-01-0246-FEDER-000010 (Multidisciplinary Institute of Ageing in Coimbra) through the COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation and Portuguese national funds via FCT - Fundação para a Ciência e a Tecnologia, under projects 2022.01232.PTDC, UIDB/04539/2020, UIDP/04539/2020 and LA/P/0058/2020. S.P.P. was supported by FCT Pos-Doctoral fellowship SFRH/BPD/116061/2016. The authors would also like to acknowledge the support of the Faculty of Psychology, Education, and Sport Sciences, Blanquerna in providing funding for Predoctoral Researchers in Training (PFU) for J.C.M. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: No potential conflict of interest was reported by the authors.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0293774#abstract0
