The
n e w e ng l a n d j o u r na l
of
m e dic i n e
Cl inic a l I m pl ic a t ions of B a sic R e se a rch Elizabeth G. Phimister, Ph.D., Editor
Braking Bad Hypertrophy Joseph A. Hill, M.D., Ph.D. The health benefits of physical activity are well documented, extending across a wide range of chronic disorders.1 In addition to improving fitness and physical strength, exercise increases caloric expenditure, which leads to decreases in adipose tissue mass. Beyond that, therapeutic effects extend to numerous chronic conditions, including mental illness (e.g., depression, anxiety, and dementia), cardiovascular disease (e.g., hypertension and atherosclerotic vascular disease), respiratory illness, osteoarthritis, osteoporosis, cancer, and metabolic disorders (e.g., diabetes and nonalcoholic fatty liver disease). Exercise may have antiinflammatory effects. The benefits of exercise are particularly evident in heart disease. Indeed, a number of studies, both preclinical and clinical, have shown significant exercise-related benefits in primary and secondary prevention. In the contexts of coronary heart disease, poststroke rehabilitation, heart failure, and prevention of diabetes, exercise interventions may provide a mortality benefit that is similar to the benefits afforded by pharmacotherapy.2 A recent study in rodent models even suggests that the effects of maternal age on the risk of congenital heart disease are mitigated by exercise.3 Indeed, physical inactivity is considered to be one of the top modifiable risk factors for death worldwide. Whereas the benefits of physical activity are apparent, the underlying mechanisms remain largely elusive. Beyond caloric expenditure with consequent beneficial effects on body weight, adiposity, and serum lipid levels, the mechanisms underlying exercise-derived benefit remain a focus of intense investigation. Physical exercise stimulates the production of soluble factors released by skeletal muscle, termed myokines. These factors, in turn, exert autocrine, paracrine, and endocrine actions. The list of myo-
2160
kines continues to grow and includes interleukins, growth factors, and substances that govern cell growth. Together, these molecules signal to skeletal muscle, the liver, adipose tissue, the heart, the brain, and blood vessels.4 As one example, it has been proposed that the so-called exercise hormone irisin is released by exercising skeletal muscle to act on white fat cells to increase their energy expenditure by means of a program of brown fat–like development (“beigeing”). Exercise triggers a robust and adaptive growth response in the myocardium. On a molecular level, exercise drives cardiomyocyte hypertrophy, as opposed to cardiomyocyte hyperplasia, notably by means of the pathway of insulin-like growth factor I, phosphoinositide 3-kinase (PI3K), and AKT1 and that of CCAAT/enhancer-binding protein β (C/EBPβ) and Cpb/p300-interacting transactivator 4 (CITED4). Some evidence suggests that the promotion of “good” heart growth antagonizes the maladaptive remodeling that is triggered by disease-related stress. A recent study by Liu and colleagues5 has shed new light on mechanisms through which exercise promotes adaptive (healthy) heart growth and blunts pathologic cardiac remodeling, unveiling a critical role for the microRNA miR-222. MicroRNAs are molecular “brakes” that bind to the 3′ untranslated regions of messenger RNA molecules, leading either to transcript degradation or repression of its translation into protein. As a general rule, microRNAs target biologic networks — such as fibrosis or cell-cycle control — by repressing multiple transcripts that code for proteins with related functions. Liu et al. provide compelling evidence that miR-222 is up-regulated by exercise and serves to brake pathologic cardiac remodeling and release the heart (“braking the brake”) to grow in a beneficial way. Consistent with this model, silencing
n engl j med 372;22 nejm.org May 28, 2015
The New England Journal of Medicine Downloaded from nejm.org at NYU WASHINGTON SQUARE CAMPUS on May 27, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
Clinical Implications of Basic Research
Pathologic Stress
Exercise
Reciprocal inhibition
Decreased levels of miR-222
Increased levels of miR-222
Adaptive growth
Adverse remodeling
Cardiomyopathy (diseased heart)
Physiologic hypertrophy (healthy heart)
Normal heart
Figure 1. Maladaptive and Adaptive Cardiac Growth. Physiological stress, such as exercise, promotes adaptive growth of the heart. Conversely, disease-related stress triggers maladaptive cardiac remodeling. Current evidence suggests that these two types of cardiac growth are mutually antagonistic and that the promotion of adaptive growth can mitigate disease-related change. In a recent study,5 the microRNA miR-222 was unveiled as a “brake” on pathways promoting maladaptive cardiac remodeling.
this microRNA promoted maladaptive heart growth, and the overexpression of miR-222 afforded additional benefit. And just as an automobile on a flat road does not move simply because one takes one’s foot off the brake — pushing on the accelerator is required — silencing miR-222 alone was not sufficient to trigger pathogenic heart growth. Current evidence suggests that the heart, in response to stress, must choose between a physiologic growth response or a path of maladaptive remodeling that ultimately culminates in cardiomyopathy (Fig. 1). If the heart chooses one path, the other is repressed. Critically, if it has already chosen the path of disease, physiological stress (e.g., exercise) can help it retrace its steps and move toward “good” heart growth. Indeed, it is fascinating that a few pathways
n engl j med 372;22
promote adaptive heart growth and at the same time block maladaptive remodeling. How is it that some stresses trigger adaptive heart growth, whereas others promote pathologic hypertrophy? Despite considerable effort to dissect these events, the underlying mechanisms remain unknown. As a lifestyle-based therapy, exercise is a powerful medicine with few nonorthopedic side effects. In reality, however, it remains a difficult medicine to administer — a regimen to which many patients cannot adhere. However, this study by Liu et al. is an important step toward dissecting mechanisms of benefit. Looking to the future, the nature, intensity, and duration of physical activity that are most effective for blunting pathologic cardiac remodeling remain to be defined.
nejm.org
May 28, 2015
2161
The New England Journal of Medicine Downloaded from nejm.org at NYU WASHINGTON SQUARE CAMPUS on May 27, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
Clinical Implications of Basic Research
Disclosure forms provided by the author are available with the full text of this article at NEJM.org. From the Division of Cardiology, University of Texas Southwestern Medical Center, Dallas. 1. Haskell WL, Lee IM, Pate RR, et al. Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the American Heart Association. Circulation 2007;116:1081-93. 2. Naci H, Ioannidis JP. Comparative effectiveness of exercise
and drug interventions on mortality outcomes: metaepidemiological study. BMJ 2013;347:f 5577. 3. Schulkey CE, Regmi SD, Magnan RA, et al. The maternalage-associated risk of congenital heart disease is modifiable. Nature 2015;520:230-3. 4. Pedersen BK. A muscular twist on the fate of fat. N Engl J Med 2012;366:1544-5. 5. Liu X, Xiao J, Zhu H, et al. miR-222 is necessary for exerciseinduced cardiac growth and protects against pathological cardiac remodeling. Cell Metab 2015;21:584-95. DOI: 10.1056/NEJMcibr1504187 Copyright © 2015 Massachusetts Medical Society.
2162
n engl j med 372;22 nejm.org May 28, 2015
The New England Journal of Medicine Downloaded from nejm.org at NYU WASHINGTON SQUARE CAMPUS on May 27, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
n e w e ng l a n d j o u r na l
of
m e dic i n e
Cl inic a l I m pl ic a t ions of B a sic R e se a rch Elizabeth G. Phimister, Ph.D., Editor
Braking Bad Hypertrophy Joseph A. Hill, M.D., Ph.D. The health benefits of physical activity are well documented, extending across a wide range of chronic disorders.1 In addition to improving fitness and physical strength, exercise increases caloric expenditure, which leads to decreases in adipose tissue mass. Beyond that, therapeutic effects extend to numerous chronic conditions, including mental illness (e.g., depression, anxiety, and dementia), cardiovascular disease (e.g., hypertension and atherosclerotic vascular disease), respiratory illness, osteoarthritis, osteoporosis, cancer, and metabolic disorders (e.g., diabetes and nonalcoholic fatty liver disease). Exercise may have antiinflammatory effects. The benefits of exercise are particularly evident in heart disease. Indeed, a number of studies, both preclinical and clinical, have shown significant exercise-related benefits in primary and secondary prevention. In the contexts of coronary heart disease, poststroke rehabilitation, heart failure, and prevention of diabetes, exercise interventions may provide a mortality benefit that is similar to the benefits afforded by pharmacotherapy.2 A recent study in rodent models even suggests that the effects of maternal age on the risk of congenital heart disease are mitigated by exercise.3 Indeed, physical inactivity is considered to be one of the top modifiable risk factors for death worldwide. Whereas the benefits of physical activity are apparent, the underlying mechanisms remain largely elusive. Beyond caloric expenditure with consequent beneficial effects on body weight, adiposity, and serum lipid levels, the mechanisms underlying exercise-derived benefit remain a focus of intense investigation. Physical exercise stimulates the production of soluble factors released by skeletal muscle, termed myokines. These factors, in turn, exert autocrine, paracrine, and endocrine actions. The list of myo-
2160
kines continues to grow and includes interleukins, growth factors, and substances that govern cell growth. Together, these molecules signal to skeletal muscle, the liver, adipose tissue, the heart, the brain, and blood vessels.4 As one example, it has been proposed that the so-called exercise hormone irisin is released by exercising skeletal muscle to act on white fat cells to increase their energy expenditure by means of a program of brown fat–like development (“beigeing”). Exercise triggers a robust and adaptive growth response in the myocardium. On a molecular level, exercise drives cardiomyocyte hypertrophy, as opposed to cardiomyocyte hyperplasia, notably by means of the pathway of insulin-like growth factor I, phosphoinositide 3-kinase (PI3K), and AKT1 and that of CCAAT/enhancer-binding protein β (C/EBPβ) and Cpb/p300-interacting transactivator 4 (CITED4). Some evidence suggests that the promotion of “good” heart growth antagonizes the maladaptive remodeling that is triggered by disease-related stress. A recent study by Liu and colleagues5 has shed new light on mechanisms through which exercise promotes adaptive (healthy) heart growth and blunts pathologic cardiac remodeling, unveiling a critical role for the microRNA miR-222. MicroRNAs are molecular “brakes” that bind to the 3′ untranslated regions of messenger RNA molecules, leading either to transcript degradation or repression of its translation into protein. As a general rule, microRNAs target biologic networks — such as fibrosis or cell-cycle control — by repressing multiple transcripts that code for proteins with related functions. Liu et al. provide compelling evidence that miR-222 is up-regulated by exercise and serves to brake pathologic cardiac remodeling and release the heart (“braking the brake”) to grow in a beneficial way. Consistent with this model, silencing
n engl j med 372;22 nejm.org May 28, 2015
The New England Journal of Medicine Downloaded from nejm.org at NYU WASHINGTON SQUARE CAMPUS on May 27, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
Clinical Implications of Basic Research
Pathologic Stress
Exercise
Reciprocal inhibition
Decreased levels of miR-222
Increased levels of miR-222
Adaptive growth
Adverse remodeling
Cardiomyopathy (diseased heart)
Physiologic hypertrophy (healthy heart)
Normal heart
Figure 1. Maladaptive and Adaptive Cardiac Growth. Physiological stress, such as exercise, promotes adaptive growth of the heart. Conversely, disease-related stress triggers maladaptive cardiac remodeling. Current evidence suggests that these two types of cardiac growth are mutually antagonistic and that the promotion of adaptive growth can mitigate disease-related change. In a recent study,5 the microRNA miR-222 was unveiled as a “brake” on pathways promoting maladaptive cardiac remodeling.
this microRNA promoted maladaptive heart growth, and the overexpression of miR-222 afforded additional benefit. And just as an automobile on a flat road does not move simply because one takes one’s foot off the brake — pushing on the accelerator is required — silencing miR-222 alone was not sufficient to trigger pathogenic heart growth. Current evidence suggests that the heart, in response to stress, must choose between a physiologic growth response or a path of maladaptive remodeling that ultimately culminates in cardiomyopathy (Fig. 1). If the heart chooses one path, the other is repressed. Critically, if it has already chosen the path of disease, physiological stress (e.g., exercise) can help it retrace its steps and move toward “good” heart growth. Indeed, it is fascinating that a few pathways
n engl j med 372;22
promote adaptive heart growth and at the same time block maladaptive remodeling. How is it that some stresses trigger adaptive heart growth, whereas others promote pathologic hypertrophy? Despite considerable effort to dissect these events, the underlying mechanisms remain unknown. As a lifestyle-based therapy, exercise is a powerful medicine with few nonorthopedic side effects. In reality, however, it remains a difficult medicine to administer — a regimen to which many patients cannot adhere. However, this study by Liu et al. is an important step toward dissecting mechanisms of benefit. Looking to the future, the nature, intensity, and duration of physical activity that are most effective for blunting pathologic cardiac remodeling remain to be defined.
nejm.org
May 28, 2015
2161
The New England Journal of Medicine Downloaded from nejm.org at NYU WASHINGTON SQUARE CAMPUS on May 27, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
Clinical Implications of Basic Research
Disclosure forms provided by the author are available with the full text of this article at NEJM.org. From the Division of Cardiology, University of Texas Southwestern Medical Center, Dallas. 1. Haskell WL, Lee IM, Pate RR, et al. Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the American Heart Association. Circulation 2007;116:1081-93. 2. Naci H, Ioannidis JP. Comparative effectiveness of exercise
and drug interventions on mortality outcomes: metaepidemiological study. BMJ 2013;347:f 5577. 3. Schulkey CE, Regmi SD, Magnan RA, et al. The maternalage-associated risk of congenital heart disease is modifiable. Nature 2015;520:230-3. 4. Pedersen BK. A muscular twist on the fate of fat. N Engl J Med 2012;366:1544-5. 5. Liu X, Xiao J, Zhu H, et al. miR-222 is necessary for exerciseinduced cardiac growth and protects against pathological cardiac remodeling. Cell Metab 2015;21:584-95. DOI: 10.1056/NEJMcibr1504187 Copyright © 2015 Massachusetts Medical Society.
2162
n engl j med 372;22 nejm.org May 28, 2015
The New England Journal of Medicine Downloaded from nejm.org at NYU WASHINGTON SQUARE CAMPUS on May 27, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
