ARTICLE
Exercise Is an Adjuvant to Contemporary Dystrophy Treatments Matthew C. Kostek1 and Bradley Gordon2 1
Duquesne University, Pittsburgh, PA; and 2Department Department of Nutrition Food and Exercise Science, Florida State University, Tallahassee, FL
KOSTEK, M.C. and B. GORDON. Exercise is an adjuvant to contemporary dystrophy treatments. Exerc. Sport Sci. Rev., Vol. 46, No. 1, pp. 34–41, 2018. Duchenne muscular dystrophy is a lethal genetic disease of muscle wasting for which there is no cure. In healthy muscle, structure and function improve dramatically with exercise. In patients with dystrophy, little is known about the effects of exercise. As contemporary therapies rapidly progress and patients become more active, there is a need to understand the effects of exercise. Key Words: muscular dystrophy, muscle, exercise training, low intensity, Duchenne
decade of life. Yet there is profound variability in the progression of the disease because there are rare cases of patients living into the fifth or sixth decade of life, although they are usually receiving full-time respiratory care. Not much is understood about this variability. Certainly, some of the variability is genetic, and at least three single nucleotide polymorphisms (SNPs) have been identified that correlate with disease severity and progression, the osteopontin (SPP1) gene (3), transforming growth factor (TGFβ) binding protein 4, and annexin A6 (4). A related disease of DMD is Becker muscular dystrophy (BMD), which also is caused by a mutation in the dystrophin gene but results in a truncated and partially functional protein product, resulting in a milder form of the disease. The genetic polymorphisms are recent enough discoveries that therapies are not modified based on these additional SNPs, although this is likely in the future. Patients afflicted by BMD are considered as having a disease distinct from DMD. Yet, in terms of understanding therapies for DMD, a closer examination of the disease variability and progression (including BMD) in our opinion has been underused. This is becoming especially pertinent because newer therapies for DMD are introduced and will likely add to the variability of the disease depending on which patients respond and how well each responds to the treatment. In the muscle cells of patients with DMD and in animal models of DMD, extensive muscle damage begins at an early age. Although we lack a complete understanding of the dystrophin protein function, it is clear that dystrophin is a critical component of muscle cell membrane stability and is essential for formation of the dystrophin glycoprotein complex and for cellular signaling (i.e., localization and function of nNOS) (5). In dystrophin’s absence, there is increased cellular membrane damage (even under light muscle tension), abnormal calcium homeostasis (which activates necrosis pathways), mitochondrial and energy balance dysfunction, increased oxidative stress, constant necrotic inflammation, and satellite cell exhaustion. Eventually, muscle cells are replaced with nonfunctional fibrotic
Key Points • Dystrophic muscle has a unique response to exercise. • High-intensity exercise can damage dystrophic muscle. • Low-intensity exercise can benefit dystrophic skeletal muscle function and improve pathology, but mechanisms are not understood. • Gene therapies and exon skipping are creating a new muscle phenotype that increases muscle function, but the effect of exercise on this new phenotype is unknown.
INTRODUCTION Duchenne muscular dystrophy (DMD) is an x-linked recessive disease that occurs at approximately 1 in 3500 live male births. The disease is the result of a mutation in the dystrophin gene that results in an absence of dystrophin protein (1). Dystrophin is an essential component of the skeletal and cardiac muscle membrane, the loss of which results in muscle cells that are easily damaged to the point of necrosis (2). Symptoms usually begin with delayed or difficulty walking, and it is typically diagnosed before age five. The muscle damage is constant and outpaces the muscles normal ability for self-regeneration through its resident population of adult stem cells (satellite cells). Adolescents with the disease are usually dependent upon a wheelchair by age 12 with respiratory failure causing death in the third Address for correspondence: Matthew C. Kostek, Duquesne University, 600 Forbes Ave, Pittsburgh, PA 15282412-396-5546 (E-mail:
[email protected]). Accepted for publication: August 21, 2017. Editor: Monica J. Hubal, Ph.D., FACSM.
0091-6331/4601/34–41 Exercise and Sport Sciences Reviews DOI: 10.1249/JES.0000000000000131 Copyright © 2017 by the American College of Sports Medicine
34 Copyright © 2017 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
collagen build up and adipose tissue accumulation resulting in loss of ambulation and eventually heart dysfunction and respiratory failure because of the loss of respiratory muscles. The tissue level and molecular pathology, like the overall body pathology, are highly variable. Currently, the standard of care for those afflicted with DMD is long-term corticosteroid therapy. As of 2016, the exonskipping oligo eteplirsen has Food and Drug Administration approval to treat DMD. It can be used to treat 13% of patients with DMD and has been able to increase dystrophin expression to near 50% of normal levels (6). Phase III trials are currently underway. Corticosteroids, the standard of care, have been shown to slow progression of the disease and extended the lifespan from the second to the third decade. Yet, these come with an array of side effects common to long-term steroid use (osteoporosis, weight gain, behavior abnormalities, diabeteslike symptoms). In short, they are less than ideal. The ideal treatment would be complete replacement or correction of the mutated dystrophin gene, likely through a form of gene therapy, either through a delivery mechanism like viral gene delivery or a gene correction through morpholinos or CRISPR technology. To date, however, these have not proven safe or effective enough in human trials except for eteplirsen. There is realistic hope that within the next 5 to 10 yr, one of these therapies will prove effective. The best of these therapies will likely be long-term treatments to be able to maintain dystrophin gene expression. The most promising therapies skip over the mutation and thus should create a Becker-like phenotype in that a partially functional dystrophin protein is produced. All of the therapies currently being studied, however, would treat only a percentage of muscle fibers, leaving other cells still carrying the mutation. And, in patients who have had the disease for many years, the treatment, muscle repair, and regeneration process will be different than that for a child who is treated before much muscle damage has occurred. Although this could dramatically extend the lifespan and quality of life, it would produce a Becker-like phenotype as opposed to a complete cure. As these treatments progress, we need to consider how future and current adjuvant therapies will interact with the new reality of the patients life and health and the new variability in pathologic levels of the disease. As treatments progress, there needs to be a renewed interest in the role of a more active lifestyle that coincides with treatments. The question of what this more active lifestyle will look like will be critical to disease treatment. And even in the face of slow progression on these treatment frontiers, the role of exercise and muscle rehabilitation should be addressed more precisely. Indeed, the role of exercise has been mostly ignored, at least as compared with most other treatments (we acknowledge that many patients with DMD do participate in some form of physiotherapy even though little is known about how to prescribe it). This is understandable considering exercise will never be a standalone treatment for the disease. Yet, an unexplored physiologic paradox with potential therapeutic benefits exists in that exercise, in healthy muscle, has a positive effect on all of the cellular and physiologic abnormalities that exist in DMD including inflammation, oxidative stress, cellular resistance to damage, energy balance, and muscle function (Figure, panel A). It is well known that in response to exercise training, most organ systems including the muscular, nervous, cardiovascular, Volume 46 • Number 1 • January 2018
pulmonary, endocrine, energy balance, and renal adapt to the specific stress of exercise. Thus, for example, skeletal muscle increases the number of contractile filaments in response to strains that overload the force producing contractile filament system. Or in response to energy deprivation, skeletal muscle increases energy production (adenosine triphosphate [ATP] generating) pathways such as mitochondrial biogenesis and overall metabolic apparatus to produce ATP. The cellular response is manifest in specific signaling cascades that result in specific physiologic adaptation. In exercise stress, the frequency, intensity, time, and type of stimulus can be varied. Modifying any of these variables individually or in some combination will alter the physiologic stimulus, in this case on muscle, and the molecular and cellular physiologic response. Another variable that is sometimes overlooked is the difference between contraction type, commonly referred to as concentric or eccentric. As typically defined, concentric contractions occur when sarcomeres shorten and, therefore, the muscle cells and the muscle itself shorten while under tension. Eccentric contractions involve lengthening of the cell/sarcomere under the same tension conditions. In most cases, the responses between the two types of contractions will make only a small difference in adaptation long term. However, eccentric contractions produce greater sarcomeric disruption, cellular damage, and inflammation than if performing only concentric contractions. Thus, muscle contraction type is likely to become an important variable in prescribing exercise for a patient with DMD. Yet, as we will currently describe, the physiologic response to exercise is altered in dystrophic muscle. As many recent investigations now report, if the intervention is of a “low” intensity, then dystrophic muscle usually is not damaged and actually responds with an improved function and cellular pathology. Why this happens, how variable it might be in patients, how it should be monitored, what the drug interactions might be, and what the exact stimulus/exercise prescription should be are unknown. Our current thesis argues that controlled low-intensity training (LIT), individualized and precisely monitored, should be considered for each patient with DMD, particularly in light of variability of the disease (partially due to SNPs) and that exercise should be considered an important adjuvant to contemporary dystrophy treatments (e.g., exon skipping). Dystrophy and Exercise: The mdx Mouse and LIT The dystrophin mutation in the mdx mouse mutation arose spontaneously in 1981 in a C57BL/10ScSn colony at University of Leicester (7). At nucleotide 3185 (exon 23), a C-to-T transition occurred, resulting in a termination codon in place of a glutamine codon. This mutation produces a truncated dystrophin protein that is mostly degraded after translation. In early life (
