Neurodegenerative disorders encompass a wide range of conditions resulting from a progressive process of degeneration of the function and structure of the central and/or peripheral nervous system [1]. Common neurodegenerative disorders include Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Among them, PD is the second most prevalent neurodegenerative disorder after AD, and the most common disorder that affects motor coordination [1]. In adults, the prevalence of PD ranges from 1 to 2 per 1000 [2]. While PD is rare before 50 years old, PD affects 2% of the population above 65 years old and 4% of the population above 80 years old [3]. Worldwide, people are living longer and the population aging is faster than in the past, so the prevalence of PD is expected to increase at an accelerated pace in the coming years. By 2040, the number of people with PD worldwide is projected to exceed 12 million [4]. Dorsey et. al. labels PD a growing Pandemic fueled by an aging population, increased longevity, and the byproducts of industrialization [5]. The annual incidence in high-income countries is 14 per 100,000 people in the total population and 160 per 100,000 people over 65 years old [3]. However, there could be several discrepancies regarding PD incidence data, probably due to methodological differences, particularly differences in case ascertainment and diagnostic criteria used [2]. A measurement of the frequency of PD is lifetime risk, which was estimated to be 2% for 40-year-old men and 1–3% for women in the United States (US) population and taking into account competing risks, such as death from other causes, including cardiovascular diseases or cancer [6]. Although the sporadic form of PD (unknown cause) is the most prevalent, around 10–15% of PD patients exhibit the familial form, resulting from a mutation in one or several specific genes [7]. Currently, at least ten mutated genes have been linked with familial PD, including α-synuclein (PARK1), Parkin (PARK2), ubiquitin C-terminal hydrolase L1 (UCH-L1 or PARK5), PTEN-induced kinase 1 (PINK1 or PARK6), DJ-1 (PARK7), leucine-rich repeat kinase 2 (LRRK2 or PARK8), ATPase 13A2 (ATP13A2 or PARK9), phospholipase A2 group VI (PLA2G6 or PARK14), F-Box protein 7 (FBXO7 or PARK15), and GRB10 interacting GYF protein 2 (GIGYF or PARK11) [8,9].

The characteristic motor and nonmotor impairments in PD patients might motivate the individuals to adopt a sedentary lifestyle, reflecting a deliberate compensatory strategy to prevent further complications, observed, for example, in patients with severe postural instability who try to avoid falls by staying indoors. Indeed, fear of falling is common in patients with PD, and might cause a reduction in their outdoor physical activities [74]. Nevertheless, this precautionary physical inactivity can have deleterious assets in several clinical domains of PD. Accumulating evidence suggests that patients with PD might benefit from PA and exercise in a number of ways, from general improvements in health to disease-specific effects, finally improving their quality of life [75]. For this reason, the ACSM has recently published several guidelines to implement exercise in PD patients in order to create a competency framework for professionals to ensure that people with PD are receiving appropriate, safe, and effective instruction and programs [27].

The different types of exercise programs that bring forward an integral impact on the physical and mental wellbeing of patients with PD include muscular relaxation and activation exercises [76], treadmill gait training [77,78,79,80], body-weight-supported treadmill training [81,82,83], and robot-assisted gait training [84,85]; virtual reality [86,87,88]; aerobic exercise training mainly stationary bicycle [89,90,91,92,93,94,95,96]; balance training [97,98]; exercise + games = exergames [99,100]; high-intensity eccentric resistance training [101]; progressive resistance training [102]; and qigong, tai chi, tango, and yoga [103,104]. The impact of most of these interventions also translates into improved quality of life [81,84,92,98,101,103,105,106,107].

Scientific evidence increasingly reinforces exercise-based interventions as a benchmark for slowing down the neurodegenerative processes associated with PD [105,106,108]. Modest tendencies towards the decrease in oxidative stress and the increase in antioxidant capacity in PD patients have been shown after a resistance training program [107]. Two biomarkers of oxidative stress (malondialdehyde (MDA) and hydrogen peroxide (H₂O₂)) were reduced after exercise training (15% and 16%, respectively), highlighting the capacity of the structured physical exercise to improve the oxidative state in people with PD [107].

Batouli and Saba concluded that a large network of brain areas, equivalent to 82% of the total volume of gray matter, was modifiable by PA [109]. The hippocampus was the brain region most affected by exercise [109]. Furthermore, exercise influences neurogenesis in the hippocampal dentate gyrus [110]. According to the prion hypothesis, α-synuclein spreads through neuronal connections and glia [111]. This propagation in the fourth stage of neuropathological course related to PD [112] reaches the hippocampus [113], producing changes in the proteins associated with synaptic structures and altering neuronal communication and function [114]. Owing to compensation and plasticity effects, during the progression of PD, training in daily living activities has been shown to restore neural circuits for movement, allowing intact nervous systems [115]. Where they can be key, there exist the cortico-ponto-cerebellar-thalamic-cortical circuits and/or cerebellum-thalamus-ganglia circuits [115], especially in the prodromal period in which non-motor manifestations are described [114,116], because, in stage III, motor symptoms appear as a result of damage in the SNpc [112,114].

Some limitations exist to specifying which symptoms respond to exercise, namely the fact that a large number of clinical trials have exclusion criteria in their design that do not allow further study of some of the symptoms and associated comorbidities. In this sense, subjects with orthostatic hypotension, dementia, and comorbidities such as stroke and degenerative osteoarthritis are normally excluded [107]. According to the ACSM, apathy, depression, and fatigue are some of the non-motor symptoms in PD, which can hinder the patient’s ability to participate in physical exercise interventions. Although the benefits of engaging in PA are known, these and other non-motor symptoms are often overlooked and underdetermined when a patient is encouraged to exercise.

For a long time, PD was perceived as a brain disease with neurodegenerative deterioration [117,118]; today, PD is seen as a multiorgan and multisystemic pathology [117,118,119]. Therefore, exercise becomes a strong ally, where accumulating evidence shows that the role of muscular secretory activity, such as adaptation to regular exercise, is crucial [26]. Thus, exercise is responsible for both systemic [120] and neural plasticity [121]. This is achieved and developed by the plasticity of the skeletal muscle that has repercussions at the cellular and molecular level [122,123].

The skeletal muscle is an endocrine organ capable of secreting a variety of neurotrophic factors with neuroprotective and beneficial effects [124]. For example, neurological disorders, impaired cognition, dementia, and depression are associated with lower levels of circulating brain-derived neurotrophic factor (BDNF), which can be mitigated by exercise [125]. BDNF release during muscle contraction reaches the brain and binds to tropomyosin receptor kinase B (TrkB), inducing the phosphorylation of several signaling pathways, including phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target rapamycin (mTOR), PI3K/AKT/mTOR pathway, PI3K/extracellular signal-regulated kinase (ERK)/cAMP responsive element-binding protein (CREB), and Pi3k/ERK/CREB pathway [126,127]. The activation of these signaling pathways leads to the secretion of additional BDNF. Moreover, BDNF promotes the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), which is the master regulator of antioxidant defense systems protecting brain cells from oxidants, inflammatory agents, and electrophiles. Nrf2 system was also implicated in mitochondrial biogenesis and mitochondrial quality control as well with protein homeostasis and cellular redox [126,127].

Exercise-induced cathepsin B release from skeletal muscle elevates BDNF abundance in the hippocampus, which has been linked to neuroprotection and improved memory function [128]. Many of these molecular adaptations are mediated by PGC-1α [120].

PGC-1α coordinates the transcription of several biological programs, including mitochondrial function, oxidative metabolism, and Ca²⁺ homeostasis [129], and is also involved in the control of various myokines [130]. PGC-1α increase also leads to the biosynthesis of kynurenine aminotransferases, thus preventing its toxic accumulation in the brain [131]. In addition, it has been shown that exercise enhances neuronal gene expression of fibronectin type III domain-containing protein 5 (FNDC5), whose protein product could stimulate brain-derived neurotrophic factor in the hippocampus [132]. The endocrine property of muscle cells also includes the release of cytokines (e.g., IL-6) or metabolites (e.g., lactate) [131].

Actually, muscle–brain crosstalk is mediated by myokines and metabolites released by muscle, but the brain also senses exercise indirectly through secretion of adipokines and hepatokines, which can cross the blood–brain barrier [133]. Exercise induces the secretion of the hormone adiponectin derived from adipose tissue, which improves hippocampal neurogenesis and has relevant antidepressant effects [131,134]. In addition, exercise promotes molecules derived from muscle and liver to enter the brain and send signals to receptors located on endothelial, glial, or neuronal cells, thereby triggering the expression of vascular endothelial growth factor (VEGF) and BDNF, key regulators of brain vascularization and plasticity [131], mediating the effects of exercise on the brain. Thus, the identification of exercise-related factors that have a direct or indirect effect on brain function has the potential to highlight new therapeutic targets for neurodegenerative diseases and cognitive enhancers for people of all ages [135].

Information about the specific molecular mechanisms occurring in PD patients’ brains and its modulation by PA is limited, as the study of the human nervous system encounters great difficulty because of its inaccessibility in living patients. Suitable healthy and “only PD” human tissues, uncomplicated by confounding pathologies, are very rarely, if ever, available to investigate. Human brain samples are obtained at autopsy in pathological situations after a variable period without functioning circulation that can markedly influence the amount and state of biomolecules [136]. In addition, cell and animal models do not fully reproduce the pathologies or phenotypes associated with old age [137]. For this reason, the use of peripherally accessible tissues, such as skin cells, has gained interest, making it possible to evaluate mitochondrial bioenergetic defects, to correlate the severity of the symptoms, and to search for biomarkers of the pathogenesis in PD [19,20,138,139].

Physical activity and exercise affect mitochondrial dynamics and function in all organs in a number of ways that may vary depending on exercise intensity. Acute exercise activates a number of pathways related to PGC-1α, which controls mitochondrial biogenesis through Ca²⁺/calmodulin-dependent protein (CaMK), p38 mitogen-activated protein kinase (MAPK), AMP-activated protein kinase (AMPK), and tumor suppressor protein 53 (p53) signaling. For instance, an increase in cytosolic Ca²⁺ induces PGC-1α, Nrf1, Nrf2, and mitochondrial transcription factor A (TFAM) in L6 myotubes [140]. Further, by increasing PGC-1α promoter activity, the p38-MAPK pathway is also able to induce mitochondrial biogenesis [141]. Additionally, it has been demonstrated that electrical stimulation and exercise result in an increase in AMPK activity [142,143].

The tumor suppressor p53 is also involved in the regulation of mitochondrial biogenesis in cardiomyocytes [138]. Several studies demonstrate that p53 deletion reduces mitochondrial respiration and content decreasing endurance [138,139,144]. In particular, p53 controls mitochondrial respiration by disrupting the equilibrium between glycolytic and oxidative pathways, by translocating to mitochondria and activating TFAM [145,146]. The mechanism appears to be reliant on the amount of training received [147]. In fact, healthy males who performed sprint interval training experienced a considerable increase in their muscle fibers’ maximal mitochondrial respiration, which was correlated with an increase in PGC-1α and p53 levels [147]. Overall, these findings imply that exercise activates different intracellular pathways that favor mitochondria biogenesis, depending on training intensity.

Physical activity and exercise have also been shown to control mitophagy and lysosome biogenesis in cardiac mitochondria [148]. Through promoting mitochondrial turnover, exercise enhances mitochondrial quality and function [148]. For example, acute exercise triggers autophagy in skeletal and cardiac muscle and exercise training induces the selective macroautophagy aimed to remove damaged mitochondria (mitophagy) [148]. As AMPK increases autophagy and given that exercise can induce AMPK, exercise likely induces mitochondrial turnover by activating AMPK-dependent mechanisms [148].

One hallmark of mitochondrial dysfunction is altered mitochondrial morphology a process finely regulated by fusion and fission processes [149]. Exercise affects mitochondrial morphology by activating specific molecular mechanisms. For example, the muscle-specific gene Zmynd17 (MSS51 mitochondrial translational activator) is known to control mitochondrial quality in muscle, especially in fast glycolytic muscles [150,151]. It has also been shown that acute exercise increases mitofusins’ expression in skeletal muscle and stimulates mitochondrial fusion by activating the PGC-1α/ERRα pathway [146]. PGC-1α overexpression in muscle leads to dense mitochondria, increasing endurance [152]. It has been reported that different exercise protocols induce mitochondrial fusion and increased mitofusin 2 (MFN2) [153]. Similarly, following exercise in healthy and moderately active subjects, dynamin-related protein 1 (DRP1) and MFN2 gene expression levels rapidly increased [154,155,156]. In this line, several studies show that acute exercise reduces mitochondrial fission in a β-adrenergic-dependent manner, mainly owing to DRP1 inactivation [152]. Exercise controls fission and fusion processes in skeletal muscle, also affecting Ca²⁺ handling. Indeed, ryanodine receptor 1 fragmentation and the subsequent increase in Ca²⁺ release in the cytosol are acutely induced by high-intensity interval training [157]. Altogether, these findings suggest that exercise turns on particular intracellular pathways to correct abnormalities in mitochondrial dynamics, indicating exercise-induced intracellular plasticity.

The PA can also modulate mitochondrial function by altering the mitochondrial respiratory chain plasticity. Electrons produced in diverse metabolic reactions are channeled into the mitochondrial electron transporting chain (ETC) to power the oxidative phosphorylation process. Structurally, ETC encompasses complex I to IV of OXPHOS. ETC plasticity involves plastic changes from freely moving complexes to super-assembled structures, called supercomplexes (SCs), and vice versa [158]. Although the physiology of respiratory SCs formation is not fully understood, there is evidence that they act by minimizing the leakage of electrons, due to an increase in the channeling of the flow of electrons, making mitochondria more efficient and reducing ROS formation [158]. In fact, mitochondrial SCs plasticity has been shown to be influenced by changes in energy demand [159]. A study of physical training in sedentary older subjects showed that exercise affected the stoichiometry of SCs formation in old age [160]. Such evidence reinforces a possible role of PA and exercise in mitochondrial plasticity modulation across different tissues.

Oxidative stress has been implicated in PD [161]. As mentioned, mitochondrial SCs formation can attenuate mitochondrial ROS production. However, mitochondrial ROS production is a natural byproduct of ETC activity, accounting for approximately 90% of cellular ROS. This chronic mitochondrial ROS generation can underlie the oxidative damage in many pathologies. In particular, ROS production during exercise can have an impact on the oxidative status of the cell. Remarkably, although regular PA stimulates health improvements, severe and/or long exercise produces ROS exacerbation, as demonstrated by increased oxidative damage biomarkers in skeletal muscles and blood [36]. Depending on the mode, intensity, and duration of exercise, the amount of ROS could determine the type of response from oxidative damage to adaptive signaling responses [36].

Although all of these beneficial effects of PA and exercise on enhancing mitochondrial biogenesis and function were known in healthy subjects, it is not clear if these effects can also be obtained in individuals with PD. It is relevant to investigate the effects of different exercise protocols and durations on motor coordination, cognitive aspects, and other (non-)motor symptoms, having mitochondrial performance as a surrogate pattern for the same cohort, and thus be able to verify how an exercise-boosted mitochondrial remodeling impacts the quality of life of patients with PD. By determining mitochondrial biogenesis signaling (PGC-1α, Nrf1, and TFAM), mitochondrial structure (oxidative phosphorylation system protein levels and SCs), mitochondrial network morphology, and mitochondrial respiratory capacity in PD patients, it would be possible to correlate with signs of improvements in motor behavior and quality of life. These studies may enable the characterization of the neuroprotective and motor effects of exercise mediated by mitochondrial modulation specifics of PD patients.