“To enjoy the glow of good health, you must exercise.” Gene Tunney
“Lack of activity destroys the good condition of every human being” Plato
Introduction: When we were growing up, we had shortcuts to reading the big classic books; we had “Cliff Notes.” Our teachers hated them because it was one person expressing their opinion. Personally, I never read a Cliff Notes, opting for the more traditional function of actually reading the book assignment. They still exist but under a different name; today, they are “CliffsNotes.” I thought for a moment about using CliffsNotes in the title of the blog post, but I decided it was not worth the effort linking it with one of my published articles. I opted for a simple beginning, “Ten Summary Points.”
“A good goal is like a strenuous exercise – it makes you stretch.” Mary Kay Ash
My Latest Publication: Being a retired academic professor has been a struggle because I still think that there are things I can contribute to related to Parkinson’s. Before I retired in 2022, I went through a three-year phased-retirement plan, moving from a full-time professor that had a research laboratory, teaching in the undergraduate and medical school curricula, and serving on several administrative committees to a 50% position focused on only education and scholarship (Parkinson’s and STEMM). The idea was to take a few years to ‘adapt’ and ‘adjust’ to working part-time with the notion that 3-years down the road, you are ready to retire. Well, it worked partially (click here to see my updated list of scholarship in Parkinson’s and education). However, I am still going to try to write, submit, and publish a peer-reviewed paper per year. Thus, I proudly present my 2024 project in the latest publication:
Mitchell, Alexandra K., Rebecca R. Bliss, and Frank C. Church. “Exercise, Neuroprotective Exerkines, and Parkinson’s Disease: A Narrative Review.” Biomolecules 14, no. 10 (2024).
Website: https://www.mdpi.com/2218-273X/14/10/1241
PDF Version: https://www.mdpi.com/2218-273X/14/10/1241/pdf
[This is an Open Access publication, so it is free to anyone to download)
The goal of this blog post is to summarize this 50-page article. Yes, it is long and full of details, and some of these details may appeal to others differently than others. Keeping in mind many different kinds of people may read the article (and this blog), including people-with-Parkinson’s, Care Partners of someone with Parkinson’s, physical therapists (and other career healthcare providers), scientists and clinicians who study/treat Parkinson’s, and other people who are interested in reading about/supporting their friends/relatives/colleagues with Parkinson’s.
“Take care of your body. It’s the only place you have to live.” Jim Rohn
#1. “Abstract” and “Introduction”: Pages 1-3 of the paper. One way to start trying to grasp any publication is to start at the beginning. I would highly recommend reading the Abstract because it summarizes the entire paper in <250 words. The Abstract tries to convey the importance of what the paper contains. We end the Abstract with these words: “In conclusion, exercise and exerkines together create a powerful neuroprotective system that should contribute to slowing the chronic progression of PD.”
Then look over the Introduction because it presents in a little more detail the primary components of the paper: (i) Parkinson’s disease and neurodegenerative disorders; (ii) Exercise; and (iii) Exerkines. We said this about exercise and neurodegenerative (ND) disorders: “Interestingly, exercise improves the symptoms of many neurodegenerative disorders, especially PD and AD [13–23].” And do not forget to look over the two figures in the introduction because they further summarize some of the key points about Parkinson’s (Figure 1) and Exercise/Exerkines (Figure 2). We said this about exercise, exerkines and brain health: “This systemic release of exerkines facilitates communication between the brain and other organs, especially the skeletal muscles that produce myokines [19,58–60]. Through this communication, exercise and exerkines work together to protect the brain, providing a natural strategy to prevent brain diseases and to improve mental health (Figure 2).”
“Exercise: you don’t have time not to.” George A. Sheehan
#2. The first part from 2. “Exercise as Therapy for Parkinson’s Disease”: The goal for this part of Section 2 is to give a narrative overview of the benefits of exercise in treating Parkinson’s (pages 2-7 of the paper). We begin with a review of aerobic exercise (endurance-based) and resistance training (strength-based) activities regarding motor- and non-motor-symptoms. We finish this part of section 2 by discussing the importance of neuromotor exercises that help improve gait and posture and lower the risk of falls (page 7 of the paper). This is followed by the importance of stretching and flexibility exercises to reduce muscle rigidity page 8 of the paper).
We said this about aerobic exercise: “Aerobic exercise enhances cardiovascular and respiratory function, leading to better overall fitness, improved functional capacity, and increased endurance for daily activities. The American Physical Therapy Association (APTA), in their clinical practice guideline on Parkinson’s disease, encourages physical therapists to implement moderate-to-vigorous-intensity aerobic exercise (approximately 60–85% HRmax) to improve oxygen consumption (VO2), reduce motor disease severity, and improve functional outcomes [76].”
We said this about resistance training: “Resistance training constitutes a fundamental component of exercise interventions for PwP, aiming to improve muscle strength, endurance, and functional capacity [94]. By targeting specific muscle groups affected by PD-related rigidity and weakness, resistance training contributes to mitigating motor symptoms and enhancing overall physical performance [95].”
We said this about neuromotor exercises: “Balance and gait training with neuromotor exercises are crucial components of physical therapy for individuals with PD, aiming to improve postural control, walking ability, and fall prevention. Attempting to normalize movements is an essential goal of neuromotor exercises and contributes to QoL issues with PwP.”
We said this about Stretching and Flexibility Exercises: “Muscle stiffness (rigidity) is a prevalent motor dysfunction in PD [141–143]…Furthermore, PwP must understand the critical negative impact of muscle rigidity an the potential benefits of managing rigidity through stretching and flexibility exercises, which can, at minimum, improve the QoL.”
“An early-morning walk is a blessing for the whole day.” Henry David Thoreau
#3. The second part from 2. “Exercise as Therapy for Parkinson’s Disease”: The part of the story begins like this: it is easy for me to tell you, “Go exercise; it is good for you, and your Parkinson’s.” However, it is better to review the literature and support this comment with documented statistics and studies proving that exercise is good for you and can help control Parkinson’s; see Section 2.6. “Review of Systematic and Meta-Analyses Studies of Exercise for treating Parkinson’s Disease.” This section presents more than 12 published studies (pages 8-10 of the paper). Simply put, there has been a lot of information published on exercise and Parkinson’s, and in summarizing these papers, we have provided substantial evidence that exercise should be considered a front-line treatment for Parkinson’s.
The second part of this story goes like this: exercise improves the Central Nervous System and, in particular, the motor unit in Parkinson’s. Our belief in this statement is solidified by reviewing the literature highlighted in Section 2.10, “The Effect of Exercise on the Central Nervous System (CNS) and Motor Unit in Parkinson’s Disease.” We provide evidence from published work that exercise enhances the CNS, and that exercise improves motor function (Pages 16-17 in the paper).
“I do it as a therapy. I do it as something to keep me alive. We all need a little discipline. Exercise is my discipline.” Jack LaLanne
#4. The third part from 2. “Exercise as Therapy for Parkinson’s Disease”: Section 2.7 “Exercise Suggestions,” (pages 10-11 of the paper contains a summary statement of sorts in what we and others recommend for how much exercise someone with Parkinson’s should do in treating Parkinson’s. Please carefully read the three paragraphs that begin section 2.7 because they try to justify and explain our goals here.
“Aerobic exercise– A moderate-to-vigorous intensity of 60-85% individualized HRmax for at least 120-150 min/week (40-50 min a day, 3 days a week) is recommended in early-stage PD. Early-stage PwP should start at 60% HRmax and, over time, aim high to reach 85% HRmax. We encourage moderate-stage and advanced-stage PwP to strive for these moderate-to-vigorous intensity levels. However, for others, moderate intensity of 50-70% HRmax for 120-150 min/week (40 min a day, three days a week, or 30 min a day, five days a week) is advised for moderate-stage to advanced-stage PD [103,154,155].
Resistance Training—It is recommended to implement a progressive resistance training regimen, working up to 60-80% of maximal effort with 3 sets of 10 repetitions two days/week for early-stage PD and 50-69% of maximal effort with 1 to 3 sets of 10 repetitions two days/week for moderate- to advanced-stage PD. These exercises are designed to improve muscle strength and function, which are often affected by PD [98,103,155,167].
Neuromotor Exercises– Patients with PD can significantly improve their Quality of Life (QoL) by incorporating the neuromotor exercise routines/programs they enjoy.
Stretching and Flexibility Exercises- It is important to include stretching and flexibility exercises in this routine. These exercises are designed to help reduce rigidity and are essential to a comprehensive exercise plan.”
And for anyone that prefer a visual learning aid, here is Figure 3 from the paper, and how we introduced it. “Figure 3 and the details above are a guide to help the PwP and Care Team (physicians and physical therapist) develop a personalized exercise plan.”
“It’s good to always do some sort of exercise.” Ashley Scott
#5. The final part from 2. “Exercise as Therapy for Parkinson’s Disease”: Section 2.8. “Strategies for Overcoming Barriers to Exercise in People With Parkinson’s Disease” details all the obstacles people must overcome to exercise. We feel that there are very few reasons a skilled physical therapist can’t manipulate the exercise routine to help most, if not all, PwP. If you have struggled with barriers preventing exercise, read this section (Pages 12-15 in the paper). If some solution has been described for your barrier, bring the solution up to your physical therapist and neurologist. Our theme is that everyone has their own personal exercise routine. Why? Because we may share the same disease, how it progresses from within is different for each of us. To illustrate these vast differences between PwP, we provide a representative overview of 6 patients and their various exercise programs (pages 14-15 of the paper).
We said this about overcoming barriers to exercise in PwP: “Rafferty et al. [171] identified a cohort in the National Parkinson Foundation Quality Improvement Initiative (NPF-QII) that showed in a two-year study that early exercisers have improved outcomes compared to sedentary individuals. Therefore, it is prudent that sedentary individuals who receive a diagnosis of PD are referred to a physical therapist who specializes in PD to initiate an exercise routine specific to the individual.”
Regarding barriers to aerobic exercise we said: “However, some individuals with PD may face barriers that limit their ability to participate in vigorous-intensity aerobic exercise at the recommended frequency and duration. These factors may include medical comorbidities, mobility, cognition, motivation, and environmental considerations. The potential for improvement in symptoms, overall health, and QoL with aerobic training warrants participation in whatever the individual can do safely [168,172].”
Regarding barriers to resistance training we said: “Resistance training will benefit from modifications tailored to the individual’s needs or level of disease progression to improve participation and safety. For example, PwP with balance challenges will find seated resistance machines safer than free weights. Individuals primarily in wheelchairs may utilize ankle weights or resistance bands as part of a seated strengthening program.”
Adapting neuromotor exercises, we said: “Of all the domains for exercise, agility, balance, and related activities may require the greatest consideration to ensure safety and an appropriate level of challenge.”
Adapting stretching and flexibility exercises, we said: “Individuals with mobility challenges, particularly those who rely on an assistive device or wheelchair, may be challenged to incorporate flexibility training. However, mobility training is particularly important for these individuals to prevent contractures that can occur with prolonged sitting.”
“Exercise is labor without weariness.” Samuel Johnson
#6. Section 3 “Exercise-induced Neuroprotective Exerkines.” Section 3 describes the putative neuroprotective role of exerkine (pages 17-24 of the paper). Remember, exerkines are molecular substance released from numerous organs and tissues during exercise and into the bloodstream. Some exerkines are destined for the brain and circulate through the bloodstream, encounter and get past the blood-brain barrier, and activate specific targets. The exerkine is the ligand, and the cell-surface-derived receptor is the binding partner. There are two ways to learn about exerkines; the first is to explore Table 2. Alternatively, there are brief reviews about each of the exerkines that detail their origin, their primary site of interaction, and signaling pathways that are involved,
“A strong body makes the mind strong.” Thomas Jefferson
#7. Section 4. “Factors that Modulate the Production of Exerkines:” In thinking about Parkinson’s, this section aimed to compare different factors that might influence the production of exerkines from exercise (pages 24 -26 of the paper). We considered four factors:
- Aerobic vs. versus resistance training
- The influence of age
- Muscle wasting
- A sedentary lifestyle
The exercise type impacted exerkine production; however, several vital exerkines were produced in both aerobic and resistance training by comparing Table 3. Regarding the type of exercise, we said: “Both exercise modalities provide substantial health benefits, but there are differences; aerobic exercise is better for reducing cardiovascular risk factors, and resistance training is better for maintaining primary metabolism and muscle mass and function, especially in older adults.”
As expected, advanced aging diminished some exerkine production; however, when re-engaging in exercise, the human body responded by producing exerkines. We said this related to aging and exerkines: “Advanced age is the most significant risk factor for developing PD [373]. Mild cognitive impairment (MCI) is linked to an irregular aging pattern that can lead to dementia, with a risk of developing further into Alzheimer’s disease (AD) [374]…To better understand the mechanism of exercise in treating MCI, Tsai et al. [375] compared aerobic exercise and resistance training in neurocognitive performance in older adults with MCI…They concluded that neuroprotective exerkines were operational in older adults with MCI, which suggests that exercise-dependent plasticity is possible [375].”
Sarcopenia happens in most adults, but it happens more frequently in Parkinson’s’. Again, there is diminished production, although there was increased production when engaged in exercise. We said this about sarcopenia and exercise: “Frequently, with advanced aging, adults can suffer a significant loss of skeletal muscle mass, which results in a disorder called sarcopenia [377,378]…They (Kwon et al.) concluded that it is critical to develop combined aerobic exercise and resistance training programs for aging adults [379].”
Furthermore, sedentary behavior is favored in Parkinson’s, and like the other scenarios, it results in reduced exerkines. However, when re-engaging in an exercise program, exerkine production increased. Regarding a sedentary life-style and exercise, we said: “PD can promote a sedentary lifestyle in older adults [382]. They ( MacNeil et al.) concluded that sedentary older adults have a lower aerobic capacity and muscle function, which implies that the lack of change in myokines released into the bloodstream was likely due to the reduced force of muscle contractions [383]. This study reinforces the notion that well-planned exercise programs can potentially help manage a sedentary lifestyle.”
The important take-home message is that exercise continues to make exerkines in advanced age, reduced muscle mass, and sedentary behavior. All one has to do is begin some sort of exercise routine (it could be either aerobic exercises or resistance training, or better yet, doing both).
“The secret of getting ahead is getting started” Mark Twain
#8. Section 5. “The Neuroprotective Theory to Slow the Progression of Parkinson’s Disease.” (pages 26-30 of the paper). The goal of this section was to introduce the neuroprotective theory, and how exercise combined with exerkines can mount a charge against the neverending Parkinson’s assault on the human brain. The section begins with describing the neuroprotective theory, and the entire idea depends on believing this statement: “Increasing evidence indicates both preventive and therapeutic functions for exerkines (292, 293).” This does not explain why the neuroprotective theory works for many individuals who will never get Parkinson’s; somehow, the mechanism has failed to protect those who develop Parkinson’s. However, there is evidence that exercise induces exerkines production and allows the PwP to mount an attack against Parkinson’s. The major signaling pathways from aerobic exercise and resistance training are discussed next. And importantly, as we noted (page 27 of the paper) “The combination of aerobic exercise with resistance training offers neuroprotection for the brain [27,73,150,411-44], and benefits the entire body and other tissues/organs [415-417]. This powerful synergy of both types of exercise underscores the potential for comprehensive health improvement.”
We then presented Table 4 (page 28 of the paper), which describes the effect of myokines (exerkines produced by skeletal muscle) in vitro and in vivo results using various Parkinson’s models. This is the crux of the information relating exerkines to Parkinson’s, unlike Alzheimer’s and neurocognitive disorders, where there is substantially more research.
We finish section 5 with a discussion of the potential role of exerkines in the brain and how they could coordinate an attack to manage Parkinson’s (pages 28-29 of the paper). The process is not trivial, and it certainly is not easy to follow, but inspecting Figure 4 gives one a collective sense of the process combining exercise and the generation of neuroprotective exerkines. Ultimately, the notion is that when someone exercises a lot and generates a generous amount of exerkines, the brain can achieve increased production of crucial growth factors (BDNF and GDNF), increased neurogenesis, increased neuroplasticity, improved cognition/memory, reduced neuroinflammation, reduced aging and oxidative stress, reduction in levels of depression and anxiety, all combine with increased energy utilization. If one combines all of these powerful actions of exerkines from sustained moderate-to-vigorous exercise, then it is reasonable to think that exercise can help manage the progression of Parkinson’s.
“Energy and persistence conquer all things.” Benja.min Franklin
#9.Sections 6 and 7, “Strengths, Limitations, Challenges,” and “Conclusions:” We conclude the paper (pages 30-31 of the paper) with two sections that try to summarize the reasons for writing this review, what were some of the limitations found in this review and what remains the challenge for those interested in exercise and exerkines in treating Parkinson’s.
We concluded the paper by saying a few things collectively about managing Parkinson’s:
•”The concept of exercise as medicine is ancient [1,2,452]. “
•”We presented the ability of exercise-induced exerkines to provide neuroprotection to reduce the risk of PD and offer neuroprotection and possibly neuro-restoration for those afflicted with PD.”
•”The diverse nature of PD and the varying progression rates found in PwP necessitate tailored management strategies. Additionally, PwP may present with different levels of physical fitness, further complicating their physical and mental health management.”
•”We wrote this review to assist Care Teams (both professional and personal) in understanding the role and application of exercise (aerobic exercise, resistance training, neuromotor exercise programs, and stretching/flexibility exercises), and in developing comprehensive and personalized management plans for PwP. “
•”Furthermore, by highlighting the molecular and physiological properties of exerkines, the Care Teams and PwP can gain knowledge and appreciate this neuroprotective process empowered by exercise.”
“Let exercise alternate with rest.” Pythagoras
#10. The Quotes Used in the Paper (pages 1-31 of the paper): It is unusual to use quotes in a scientific paper. Yet, I thought the quotes used conveyed a sense of history regarding exercise for maintaining good health. Importantly, many of us think that it is only recent we have we embraced the idea that “exercise is medicine.” In fact, it is an ancient idea that keep making its rounds to the current time. Maybe, if we can collectively believe it, the world’s burden with Parkinson’s will become more manageable. And these quotes just resonated with me as being the right ones to include in this paper. They just seem to fit in well in the various sections. The quotes used are as follows:
Summary: I hope you enjoy the breaking down of this article. In the past, I have done it for other articles, but never one of my own. It took a long time to organize and write this article. My two co-authors, Alex Mitchell (a former student in my undergraduate “Blood Diseases” course, and a recent graduate of the UNC-CH Physical Therapy program) and Dr. Rebecca Bliss (a former physical therapist of mine when I lived in North Carolina) contributed much to the manuscript, and I appreciated their efforts to compose their sections. It is never easy writing a paper together, and they were wonderful co-authors who were steadfast in their belief in this paper. They also served as a great sounding board to keep me in check, especially as I would wander off-track and try to expand down areas that were not ready to be written about, So I am very thankful for their effort on this paper.
“The hopeful goal is that exercise will give you healthier lives, allowing you to negotiate a better life on your terms, not Parkinson’s. These observations about exercise and brain disorders are vital because they genuinely reflect the importance of exercise in treating Parkinson’s.” Frank C. Church
Cover Photo Image by Rick Wunderle from Pixabay
Journey with Parkinson's 