A Special Regenerative Rehabilitation and Genomics Letter: Is There a “Hope” Molecule?

We are delighted to see the dedication of a special series to regenerative rehabilitation and genomics. There is no doubt that an increased focus on genetically driven responses to injury, disease, and aging will enhance prevention and treatment efforts for a number of conditions. Among those well-positioned to benefit from this progress are individuals with mood disorders, which has prompted us to alert our colleagues about recent progress in elucidating the molecular mechanisms that underlie musculoskeletal and central nervous system interdependence, knowledge that may be deployed to prevent and treat stress-related depression in the near future.

Depression is a pervasive health problem that includes emotional, psychomotor, cognitive, and biorhythmic disturbances. Current estimates suggest that this disorder has a 1-year prevalence of 9% of the US population.¹ Of those affected, 42% report severe functional impairments; in contrast, 24% of people with chronic medical disorders report severe functional impairment, underscoring a significantly higher degree of impairment for those with mood disorders.² Depressive symptoms are associated with a higher risk of all-cause mortality^3–6 and a 20-fold increase in the risk of suicide.⁷ Approximately half of patients with pain in the physical therapy setting demonstrate symptoms of depression.^8,9 Notably, depression is expected to be the second-greatest health burden in terms of quality-adjusted life-years by 2020.¹⁰ The direct and indirect costs of treating depression are staggering, amounting to $44 billion annually in the United States.¹¹ Limited accessibility to effective treatment options contribute to the exorbitant human and financial toll of major depression,^2,12 prompting us and others to acknowledge the need for a diversification of efforts to find feasible and effective treatment options.^12–14

Physical exercise has been suggested as a promising means of complementary care for the treatment of depression.^15,16 Epidemiological and clinical research demonstrates that exercise reduces risk for mood disorders,^17–19 degree of symptoms,²⁰ and incidence of relapse.^21,22 The putative effects of exercise include optimization of levels of neurotransmitters,²³ neurotrophic factors,^23–25 β–endorphins,^26,27 cortisol,^28,29 and growth hormone.³⁰ Moreover, recent ground-breaking work on mice has demonstrated that a muscle-derived protein (peroxisome proliferator-activated receptor C coactivator 1α [Pgc-1α]*) elicited by exercise can directly influence mood by altering brain mechanisms involved in depression.³¹

It has long been known that physical exercise increases levels of PGC-1α.^32,33 This knowledge, along with the fact that PGC-1α can significantly influence brain physiology, led to the suggestion of a direct linkage of PGC-1α to depression.³¹ Nevertheless, deriving scientific proof of this link has proven onerous because PGC-1α is expressed in a variety of systems throughout the body (eg, musculoskeletal, cardiovascular, hematopoietic, digestive, nervous), making it difficult to discern whether the effects of exercise originate from central or peripheral mechanisms. To tackle this problem, Agudelo and colleagues used mice that were genetically modified to produce excessive levels of Pgc-1α in their type II skeletal muscle fibers.³¹ The mice were then exposed to chronic stress—a method known to induce depression. Interestingly, mice overexpressing Pgc-1α in their muscles were far more resistant to depressive symptoms in comparison with mice with normal levels of Pgc-1α. The researchers then questioned what would happen if Pgc-1α levels were reduced. Mice genetically engineered to produce lower levels of Pgc-1α in their skeletal muscles were subjected to a forced-swim test. After a significant amount of stress, the mice appeared to “lose hope,” as evidenced by their decreased survival efforts during forced swimming (an indicator of depression). Altogether, these results suggest that the release of “hope molecules” from the skeletal muscles of rodents influence mood disorder symptoms. What remains to be determined is how a peripheral molecule such as Pgc-1α can drastically influence mechanisms within the brain. Although these authors suggested that central mechanisms involving kynurenine metabolism are involved, it also seems plausible that increases in Pgc-1α expression may alter levels of neurotrophins (brain-derived neurotrophic factor) within the brain and contribute to changes in structure and function (see Phillips et al³⁴), leading to a reduction in depressive symptoms.

To date, the aforementioned work has not been extended to patient populations with depression. Nevertheless, the work provides a strong theoretical basis for the idea that endurance exercise can be used to induce the release of PGC-1α from skeletal muscles to mitigate depressive symptoms. So the question arises as to whether there is currently enough evidence to support the deployment of physical activity to positively influence depressive symptoms in clinical populations. To answer this long-standing question, Cooney and colleagues conducted a meta-analysis of high-quality randomized trials published up to March 2013.¹⁵ Thirty-nine studies with a total of 2,326 participants were included in the review. The authors reported that exercise produced effects comparable to treatment by either antidepressive medications or psychotherapy. A meta-analytic study by Silveira and colleagues also demonstrated that aerobic exercise moderately reduced the signs of depression, with populations over 60 years of age deriving the greatest effect.¹⁶ Notwithstanding, there is currently little evidence to indicate which modality of exercise is optimal (aerobic, strengthening, flexibility, or combinations). In a recent meta-analytic review, Stanton and Reaburn tried to determine optimal parameters for using exercise to treat depression (eg, frequency, intensity, duration, and type of exercise). All 5 randomized controlled studies meeting inclusion criteria were aerobic in nature (walking on treadmill or outdoors, cycling on a stationary bike, or training on an elliptical machine).³⁵ Positive evidence was found that aerobic exercise of moderate intensity, undertaken 3 times weekly for a minimum of 9 weeks, was successful in treating depression.³⁵

Clearly, large-scale, multiple-site clinical investigations that study the relationship between exercise and depression are needed. The effects of Pgc-1α on phenotypic traits—such as adiposity, lean mass, and fasting glucose—and the way that they could be modulated by genetic background (ethnicity) have not been precisely understood. Moreover, the degree to which Pgc-1α polymorphisms (common variation in gene sequence) determine an individual's response is unknown. Future work that combines these measures with neuroimaging studies should be used to determine optimal “doses” of physical intervention across patient populations. Finally, strategies for overcoming core symptoms of depression—such as loss of interest, motivation, and energy; generalized fatigue; low self-worth feelings and low self-confidence; psychosomatic complaints; and comorbid health problems—need to be clearly delineated and articulated so that exercise adherence can be optimized.

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Figure.

A large body of evidence has indicated the importance of PGC-1a in a number of important biological processes. The figure suggests a role for PGC-1a in mood disorders, but this molecule also affects other key physiological processes. For instance, through acting on a number of intermediate molecules, PGC-1a plays a vital role in the maintenance of metabolic (glycogen synthesis), skeletal muscle (mitochondrial biogenesis), and cognitive functions (trophic factor release). Reciprocal interactions exist among these variables, suggesting that physical activity could play a role in therapeutic strategies that target mood, metabolic, and cognitive disorders. PGC-1a=peroxisome proliferator-activated receptor C coactivator 1α, BDNF=brain-derived neurotrophic factor, FNDC5=fibronectin type III domain-containing protein 5, NAD (+)=nicotinamide adenine dinucleotide, FBX2=F-box protein 2, NMDARs=N-methyl-D-aspartate receptors, GluN2a=glutamate receptor subunit 2a, GluN2b=glutamate receptor subunit 2b, GluA1=glutamate receptor-A1, GluA2=glutamate receptor-A2, AMPARs=α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, TNF-a=tumor necrosis factor alpha, IL-6=interleukin 6, IGF-1=insulin-like growth factor 1, GLP-1=glucagon-like peptide-1.

We contend that the aforementioned findings can be used to enrich practice and research across a number of settings, as mental and physical health are inextricably melded. Indeed, there is evidence that physical activity can be used to fundamentally change brain physiology in people with cognitive, neurodegenerative, and mood disorders.^31,35 Moreover, the fact that depressive symptoms exert a significant influence on service utilization³⁶ and clinical outcomes⁸ makes it imperative for physical therapists to stay abreast of emerging knowledge that links the reciprocal relationship between skeletal muscle activity and brain function. Doing so will ensure that we may remain steadfast in our mission to provide evidence-based practice, in conjunction with other specialists, for all people, including those with depression.

• © 2016 American Physical Therapy Association