Exercise, Neuroprotective Exerkines, and Parkinson’s Disease: A Narrative Review
Abstract
:1. Introduction
1.1. Neurodegenerative Diseases and the Positive Impact of Exercise
1.2. Parkinson’s Disease (PD)
1.3. Exercise and Exerkines
1.4. Parkinson’s Disease, Exercise, and Exerkines
2. Exercise as Therapy for Parkinson’s Disease
“Movement is a medicine for creating change in a person’s physical, emotional, and mental states.” Carol Welch-Baril, Neuromuscular Therapist
2.1. Defining Physical Activity and Exercise
2.1.1. Exercise Intensity Defined
2.1.2. Calculating Maximal Heart Rate during Exercise
2.2. Aerobic Exercise
2.2.1. Motor Symptoms
2.2.2. Brain Structure and Cognitive Symptoms
2.3. Resistance Training
2.3.1. Motor Symptoms, Disease Severity, and Motor Function
2.3.2. Non-Motor Symptoms and Quality of Life
2.4. Neuromotor Exercises to Improve Gait, Posture, Balance, and Reduce Risk of Falls
2.5. Stretching and Flexibility Exercises to Reduce Muscle Rigidity
2.6. Review of Systematic and Meta-Analysis Studies of Exercise for Treating Parkinson’s Disease
2.7. Exercise Suggestions
2.8. Strategies for Overcoming Barriers to Exercise for People with Parkinson’s Disease
2.8.1. Reworking Aerobic Exercise
2.8.2. Revisiting Resistance Training
2.8.3. Adaption of Neuromotor Exercises: Agility and Balance
2.8.4. Refining Flexibility
2.9. Examples of a Structured Exercise Strategy for Parkinson’s Disease
2.10. The Effect of Exercise on the Central Nervous System (CNS) and Motor Unit in Parkinson’s Disease
2.10.1. Exercise Enhances the Function of the CNS
2.10.2. Exercise Improves Motor Function
2.10.3. Long-Term Effect of Exercise on Parkinson’s Disease
2.11. Summary of Exercise and Introduction to Exerkines
3. Exercise-Induced Neuroprotective Exerkines
“Natural forces within us are the true healers of disease.” Hippocrates (460–375 BCE) [2]
3.1. The Association between Cardiorespiratory Fitness and the Risk of Parkinson’s Disease
3.2. Neuroprotective Exerkines
3.2.1. Adiponectin
3.2.2. Apelin
3.2.3. Beta-Aminoisobutyric Acid (BAIBA)
3.2.4. Beta-Hydroxybutyrate (BHB)
3.2.5. Brain-Derived Neurotrophic Factor (BDNF)
3.2.6. Cathepsin B (CTSB)
3.2.7. Fetuin-A
3.2.8. Fibroblast Growth Factor 21 (FGF21)
3.2.9. Glial Cell Line-Derived Neurotrophic Factor (GDNF)
3.2.10. Glycosylphosphatidylinositol-Specific Phospholipase D1 (GPLD1)
3.2.11. Insulin-like Growth Factor-1 (IGF-1)
3.2.12. Interleukin-6 (IL-6)
3.2.13. Irisin (FNDC5)
3.2.14. Lactate
3.2.15. Lac-Phe
3.2.16. miR451a and miR-150-5p in Small Extracellular Vesicles (sEVs)
3.2.17. Monoamine Neurotransmitters (Dopamine (DA), Norepinephrine (NE), and Serotonin (5-HT))
3.2.18. Peroxisome Proliferator-Activated Receptor-Gamma Coactivator (PGC)-1alpha (PGC-1α)/Kynurenine (Kyn) Interaction
3.2.19. Vascular Endothelial Growth Factor (VEGF)
3.3. Exerkines and the Ability to Cross the Blood–Brain Barrier
3.4. Summary of Exerkines
4. Factors That Modulate the Production of Exerkines
“Look to the nervous system as the key to maximum health.” Galen (130 AD–210 AD) [2]
4.1. Aerobic Exercise (Endurance-Based) versus Resistance Training (Strength-Based)
4.2. Age
4.3. Muscle Wasting
4.4. Sedentary Lifestyle
5. The Neuroprotective Theory to Slow the Progression of Parkinson’s Disease
“Your age is the sum total of your physical condition, the condition of your mind, and how you feel.” Jack LaLanne (1914–2011; LaLanne hosted the first and longest-running syndicated fitness television program in the U.S., from 1951 to 1985)
5.1. Assessing the Neuroprotective Theory
5.2. Initiation Pathways for Aerobic Exercise and Resistance Training
5.3. Neuroprotective Action from Myokines in Model Systems of Parkinson’s Disease
5.4. Neuroprotective Components Provided by Exerkines
6. Strengths, Limitations, and Challenges
“We must turn to nature itself, to the observations of the body in health and in disease to learn the truth.” Hippocrates (460–375 BCE) [2]
7. Conclusions
“The use of exercise has had an important share in the treatment of disease since Hippocrates used it at the sanitarium at Cos, and Galen advocated it in words that are as true now as they were eighteen hundred years ago…” R. Tait McKenzie, M.D. (1909) in “Exercise in Education and Medicine” [468].
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
AD | Alzheimer’s disease |
ALS | amyotrophic lateral sclerosis |
AMPK | AMP-activated protein kinase |
BAIBA | beta-aminoisobutyric acid |
BBB | blood–brain barrier |
BDNF | brain-derived neurotrophic factor |
BHB | beta-hydroxybutyrate |
Bpm | beats per minute |
CNS | central nervous system |
CTSB | cathepsin B |
DA | dopamine |
ERK 1/2 | extracellular signal-regulated kinase 1/2 |
FGF21 | fibroblast growth factor 21 |
FNDC5 | fibronectin type III domain-containing Protein 5 |
GDNF | glial cell line-derived neurotropic factor |
GPLD1 | glycosylphosphatidylinositol-specific phospholipase D1 |
GPCR | G protein-coupled receptor |
% HRmax | % maximal heart rate |
HCAR2 | hydroxycarboxylic acid receptor 2 |
H&Y | Hoehn and Yahr scale of PD stage |
6-OHDA | 6-hydroxydopamine |
IGF-1 | insulin-like growth factor 1 |
IL-1, -6, -10 | interleukin-1, -6, -10 |
Kyn | Kynurenine |
Lac-Phe | Lactoylphenylalanine |
miR | microRNA |
MPTP, MPP+ | 1-methyl-4-phenylpyridinium (Inactive/active forms) |
MCI | mild cognitive impairment |
p38 MAPK | p38 mitogen-activated protein kinase |
ND | neurodegenerative |
NE | norepinephrine |
NF-κB | nuclear factor kappa-light-chain-enhancer of activated B cells |
OT | occupational therapist |
PD | Parkinson’s disease |
PwP | people (person)-with-Parkinson’s |
PGC-1α | peroxisome proliferator-activated receptor gamma coactivator 1-alpha |
PPARα/δ/γ | peroxisome proliferator-activated receptor alpha/delta/gamma |
PI3K/AKT/mTOR | phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin |
PT | physical therapist |
PTSD | Post traumatic stress disorder |
Irisin | proteolyzed fragment of FNDC5 |
PAI-1 | plasminogen activator inhibitor-1 |
5-HT | serotonin |
SIRT1 | sirtuin 1 |
SLP | speech–language pathologist |
sEV | small extracellular vesicles |
TBI | Traumatic brain injury |
TrkB | tropomyosin receptor kinase B |
TNF-α | Tumor necrosis factor-alpha |
UPDRS | Unified Parkinson’s Disease Rating Scale |
VEGF(R) | vascular endothelial growth factor (receptor) |
WAT | white-adipose tissue |
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Individual Profile | Aerobic Exercise | Resistance Training | Neuromotor Rehabilitation Programs | Flexibility/Stretching Exercises |
---|---|---|---|---|
Eighty-year-old male with advanced PD, ambulates with a rollator and requires caregiver support. He experiences some “off times” in which his medication becomes less effective. He is highly motivated with a great family and friend network. | Rides a NuStep or recumbent bike for 40 min 3×/week. Target HR of 60–70% HRmax | Participated in a seated strengthening program with use of resistance bands for upper body and supervision of a caregiver 2×/week. Completed during “on time” of medication cycle. | Currently receiving PT once every two weeks for maintenance PT. Also receives restorative PT periodically throughout the year. Goal of working on weight shifts with his rollator alongside a trained family member 3×/week. | Participates in daily stretches in his bed before getting up in the morning. Goal of taking a Dance for PD class online 1×/week. |
Retired 70-year-old female with short term memory loss who enjoys staying active so she can spend time with her children and grandchildren | Walks 1–2 miles every day (when it is not raining). Target RPE for walks is 6/10. | Goes to the gym 2×/week and uses resistance machines after participation in exercise classes. | Receives restorative PT approximately 1–2×/year. Goal of taking 1–2 classes at her gym each week. (Varies between PWR!Moves, tai chi and Dance for PD) Sometimes her daughter will join her. | Participates in 10 min of home stretches as instructed by PT 5×/week. |
Sixty-five-year-old female who was diagnosed one year ago. She has lived a lifetime of being active and is very willing to try to explore exercise options. She is still working and will retire in 1–2 years. | Walks on a treadmill 3×-week with goal of 75% max HR and plays tennis 2×/month | Works out in her home gym using free weights 2×/week | Participates in benchmark assessments 2×/year and restorative PT as needed Participates in a mix of the following activities 1–2×/week: tennis, tai chi, golf, PWR!Moves classes | Incorporates 15 min of stretching as a cool down after her resistance workouts, 2×/week |
Recently diagnosed retired 76-year-old male with high blood pressure (controlled with medication) who is relatively sedentary, resistant to begin exercising but willing to give it a chance. He checks his BP daily. | Walks his family dog 3×/week for 20 min. He is working towards a goal of walking for 25 min. | Goal of participating in Rocksteady boxing 1×/week, Goal of completing body weight resistance exercises 2×/week during the commercial breaks of a television show he watches every day | Referred to PT to help establish an exercise program and address balance. PT will also instruct on modifications as needed to improve safety with exercise in individuals with high blood pressure. | Goal of incorporating 10 min of stretches after he gets up in the morning Goal of completing PWR!Moves seated mobility exercises 3×/week during the commercial breaks of a television show he watches every day |
Retired 70-year-old male originally diagnosed at age 59 who experiences right side stiffness, right arm tremor, controlled with Carbidopa/Levodopa, NeuPro patch; follows an integrated approach to treatment. | Rides his Peloton bike for 45 min with goal of 80% HRmax 3×/week; 3–5 mile power walk 1×/week | 30–45 min weightlifting on major muscle groups 2×/week | LSVT BIG, and regularly works with a PT for any sports-related injury | Daily stretching, and 2× week aim for PWR!Moves or RockSteady Boxing. Participates in golf 2–3×/week. |
Forty-one-year-old female who was diagnosed at age 39. She has two children ages 10 and 12 and is still working. She was previously active but not a formal exerciser. Over the past two years has worked with her healthcare team to start an exercise program that emphasizes aerobic components. | She initially used the couch to 5K program to begin running. Now participates in a running group and runs 3–5 miles 2–3×/week with target HRmax of 80%, also walks 20–30 min 2–3×/week. (She will often walk during her children’s soccer practice.) | Goes rock climbing with her son 2×/month. Goal of participating in 30 min of strength training 2×/week. She uses an online fitness membership to guide her workouts. | She worked with a PT to initiate an exercise program and participates in benchmark testing 2×/year. Returns to PT as needed to adjust exercises. Goal of participating in yoga 2×/week in addition to running. | Goal of completing a 15 min yoga video 2×/week. Goes rock climbing with her son 2×/month. |
Name | Source Tissue(s) | Target Tissue(s) | Example(s) of Biological Action | Reference(s) |
---|---|---|---|---|
Adiponectin | WAT | Brain, heart, liver, muscle | Anti-inflammatory, glucose and fatty acid metabolism | [195,196,197,198] |
Apelin | Skeletal muscle, WAT | Brain, bone, skeletal muscle | Anti-apoptotic | [48,199] |
BAIBA | Skeletal muscle | Many sites | Metabolic regulator, anti-inflammatory, anti-oxidative | [200,201,202] |
BHB | Liver | Many sites | Improves fuel utilization, anti-inflammatory | [203,204,205] |
BDNF | Brain, skeletal muscle | Brain | Enhances synaptic plasticity, and cell growth | [206,207,208,209] |
CTSB | Skeletal muscle | Brain | Neurogenesis, memory | [210,211] |
Fetuin-A | Liver | Liver, brain | Neuroprotective, anti-inflammatory | [212,213,214] |
FGF21 | Many tissues, liver, WAT | Many tissues, heart, bone, gut, brain, WAT | Improves fuel utilization (glucose, lipid) | [215,216,217] |
GDNF | Spinal cord | Brain | Maintenance of spinal motor neurons and midbrain dopaminergic neurons | [218,219,220] |
GPLD1 | Liver | Brain | Improves neurogenesis and cognition | [221,222] |
IGF-1 | Liver, skeletal muscle, and other tissues | Brain, many sites | A mediator of brain health following exercise including neurogenesis and cognitive improvement | [223,224,225] |
IL-6 | Skeletal muscle | Many sites | Energy sensor, anti-inflammatory in brain | [226,227,228] |
Irisin (FNDC5) | Skeletal muscle | WAP, bone, β-cells, brain | Promotes neuronal health | [229,230,231] |
Lactate | Skeletal muscle | Many tissues, including CNS | Brain fuel source | [232,233,234] |
Lac-Phe | Epithelial cells in gut and kidney | Many tissues, including CNS | Suppresses feeding and obesity | [235,236,237] |
mIR451a/mIR-150-5p/sEV | Skeletal muscle and other tissues | Many tissues including CNS | Protects against depression (miR-451a) and anxiety (miR-150-5p) | [238,239,240] |
Monoamine neurotrans-mitter (DA, NE, 5-HT) | Brain | Brain | DA—Motor control, learning, executive function; NE—stress resistance memory, cognition; 5-HT—relieve anxiety, stress protection, cognition | [241,242,243] |
PGC-1α/ Kynurenine | Skeletal muscle, liver, and other tissues | Skeletal muscle, and brain | PGC-1α activates kynurenine aminotransferase, switching the ratio of kynurenine (neurotoxic) to kynurenic acid (neuroprotective) | [244,245,246] |
VEGF | Skeletal muscle and other tissues | Brain endothelium and other tissues | Promotes angiogenesis and exercise-induced neurogenesis | [247,248,249] |
Aerobic Exercise [Reference(s)] | Resistance Training [Reference(s)] |
---|---|
Apelin ↑ [253,337] BAIBA ↑ [338] BDNF ↑ [339,340] CTSB ↑ [341] FGF21 ↑ [342] Fractalkine ↑ [343] IGF-1 ↑ [285,344] IL-6 ↑ [345,346] IL-15 ↑ [347] Irisin ↑ [229] Lactate ↑ [348] LIF ↑ [349] MCP-1 ↑ [343] Musclin ↑ [350] Myonectin ↑ [351] Myostatin ↓ [352] PGC-1α ↑ [353,354] SDF1 ↑ [355] SPARC ↑ [356] RANTES ↑ [216] VEGF ↑ [357] | Angiopoietin-like 4 ↑ [358] BDNF ↑ [359] BMP7 ↑ [360] CTSB ↑ [361] Decorin ↑ [362] FGF21 ↑ [363,364] IGF-1 ↑ [283,365] IL-6 ↑ [346] IL-15 ↑ [366] Irisin ↑ [364,367] Lactate ↑ [368] Myostatin ↓ [352] PGC-1α ↑ [369] VEGF ↑ [370] |
Myokine | Experimental Model | Mechanism of Action | Physiological Function | Reference |
---|---|---|---|---|
Apelin-13 | SH-ST5Y cells + MPP+ + apelin-13 | ↑ ERK1/2 phosphorylation ↓ ER stress | ↓ Cell death | [418] |
Apelin-36 | SH-ST5Y cells + MPP+ + apelin-36 | ↑ PI3K/Akt/mTOR autophagy | ↑ α-Synuclein clearance | [419] |
Apelin-36 | Mice + MPTP + apelin-36 | ↑ GSH and SOD ↓ Caspase-3 | ↓ Anti-oxidative stress | [420] |
Apelin-13 | SH-ST5Y cells + 6-OHDA + apelin-13 | ↑ PI3K ↓ Caspase 3 ↓ Cytochrome c | ↓ Cell death | [421] |
FGF21 | Mice + MPTP + FGF21 SH-ST5Y cells + MPTP + FGF21 | ↑ SIRT1-autophagy | ↑ α-Synuclein clearance | [422] |
FGF21 | Mice injected with MPTP + FGF21 SH-ST5Y cells + MPTP + FGF21 | ↑ BCL2/Bax ↓ Caspase 3 cleavage and JNK phosphorylation | ↓ Cell death | [423] |
FGF21 | Primary dopaminergic neurons + MPP+ + FGF21 | ↓ IL-1, IL-12, IFN-γ, and TNF-α ↓ Astrocyte and microglia activation | ↑ Anti-inflammation | [423] |
IGF-1 | PC12 cells + 6-OHDA + IGF-1 | ↓ Caspase-3 activation, and PARP cleavage | ↓ Cell death | [424] |
IGF-1 | Rats + 6-OHDA + IGF-1 | ↑ PI3K/Akt | ↓ Cell death | [425] |
IGF-1 | Rats + 6-OHDA + IGF-1 | ↑ ERK 1/2/CREB ↑ Akt/GSK3α/β/ β-catenin | ↓ Cell death | [287] |
IGF-1 | PC12 cells + 6-OHDA + IGF-1 | ↑ HO-1 | ↓ Anti-oxidative stress | [424] |
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Mitchell, A.K.; Bliss, R.R.; Church, F.C. Exercise, Neuroprotective Exerkines, and Parkinson’s Disease: A Narrative Review. Biomolecules 2024, 14, 1241. https://doi.org/10.3390/biom14101241
Mitchell AK, Bliss RR, Church FC. Exercise, Neuroprotective Exerkines, and Parkinson’s Disease: A Narrative Review. Biomolecules. 2024; 14(10):1241. https://doi.org/10.3390/biom14101241
Chicago/Turabian StyleMitchell, Alexandra K., Rebecca R. Bliss, and Frank C. Church. 2024. "Exercise, Neuroprotective Exerkines, and Parkinson’s Disease: A Narrative Review" Biomolecules 14, no. 10: 1241. https://doi.org/10.3390/biom14101241
APA StyleMitchell, A. K., Bliss, R. R., & Church, F. C. (2024). Exercise, Neuroprotective Exerkines, and Parkinson’s Disease: A Narrative Review. Biomolecules, 14(10), 1241. https://doi.org/10.3390/biom14101241