The scientific field of exercise physiology has made significant advances during the last 50 yr in providing knowledge products, highlighting the numerous beneficial and anabolic outcomes of physical activity with particular regard to the musculoskeletal system. The societal impact of exercise prescription guidelines that have been generated for optimal training aimed at improving physical and mental health while also mitigating injury risk is of obvious benefit to both practitioners and clinicians, as well as to the lay community. From a basic and applied scientific research perspective, however, the underlying mechanisms mediating such desirable anabolic adaptations from physical activity such as muscle hypertrophy and increased bone mineral density are, even as we enter the 21st century, still incompletely understood and much has yet to be unraveled and learned. Nonetheless, there is universal consensus that the interplay between cytokines and growth factors (i.e., insulin-like growth factor-I (IGF-I)) serves as an important mechanism mediating many of the regulatory responses resulting from physical exercise and leading to phenotypic transformations (17,22,25). However, both the biological redundancy and complexity that seem to govern such interactions and the reported contradictory literature often prevent definitive conclusions from being drawn. The intent of this symposium entitled "Insulin-like Growth Factor-I, Physical Activity, and Control of Cellular Anabolism" is to provide brief, state-of-the-art overviews underscoring the current state of the knowledge for IGF-I/cytokine influences on mediating anabolic and health outcomes from physical activity.
A common thread of all three articles presented herein is a shared focus on IGF-I, which has truly emerged as a critical anabolic and metabolic hormonal biomarker that promotes anabolism and exhibits many somatotropic influences. Although there are overlapping effects that growth factors and steroid hormones (i.e., testosterone) exert on anabolic processes (16), this symposium will focus on IGF-I. We will learn, however, that some of the IGF-I literature is paradoxical and perhaps even counterintuitive. This can largely be attributed to the ubiquitous nature, regulatory complexity, and pleiotropic actions of IGF-I. Specifically, IGF-I is produced by the liver in an endocrine fashion and can act systemically while also being produced locally by a host of cell types to act in a autocrine/paracrine fashion (2). IGF-I is also the only hormone in the body that is controlled by a family of six binding proteins that can both inhibit and stimulate IGF-I action (23). Finally, we believe that the path ahead for delineating the precise role of IGF-I for mediating cellular anabolism from physical activity lies in using an integrative approach with multiple levels of investigative inquiry: transgenic animal models that manipulate the IGF-I gene (i.e., the liver IGF-I-deficient mouse) (30), Western blotting and real-time polymerase chain reaction techniques to assess IGF-I protein content and mRNA expression (6,26) involved with intracellular signaling (2), minimally invasive technologies to sample IGF-I various biocompartments (i.e., microdialysis) (7), novel assay procedures to measure biologically active form of IGF-I (i.e., the kinase receptor activation cell bioassay) (10), and prospective experimental research designs. The precise relationship between systemic and local IGF-I has yet to be fully described and understood.
For the first paper in this symposium proceedings, a leading researcher in the area of IGF-I measurement and assessment, Jan Frystyk (13) from Aarhus University in Aarhus, Denmark, presents "The relationship between exercise and the growth hormone-insulin-like growth factor-I axis," in which he overviews the current literature concerning acute and chronic exercise with special consideration given to the measurement of total, free, and bioactive IGF-I. Frystyk's laboratory has made contributions to the field of IGF-I biology by validating two separate assays for the measurement of IGF-I. Frystyk et al. have developed an ultrafiltration by centrifugation method to detect "free IGF-I" (14) as well as a cell culture-based bioassay (kinase receptor activation assay) for the measurement of bioactive IGF-I (10). These specialized assays provide a different and perhaps superior biological dimension for assessing IGF-I biology through providing insight into IGF-I/receptor interactions; however, few studies have evaluated bioactive IGF-I within the context of exercise paradigms (15). In addition, Frystyk highlights the only three currently available studies that have exploited microdialysis techniques for the measurement of IGF-I during exercise (7,11,21). Whereas microdialysis possesses the advantage of allowing for a preview of altered biochemistry in the interstitial fluid of cells and tissues before systemic changes can be observed and has been accepted as a valid approach for many years, it was not until recent investigations that the procedure has been used to monitor growth factor responses in muscle and tendon from physical exercise. Incorporation of these measurement and sampling technologies will be increasingly used in the coming years and will provide greater insight into IGF-I physiology.
Although IGF-I is known to be under the direct regulation of growth hormone (GH), and GH robustly and consistently increases during and after exercise, the literature on increased IGF-I after exercise is more equivocal. Increases, decreases, and no changes have been reported after both acute and chronic exercise perturbations. Much of these findings can be attributed to differences in the exercise protocols and subject characteristics. Finally, Frystyk provides a timely summary on exercise studies that have included either free or bioactive measurements of IGF-I. In contrast to the equivocal results from the exercise literature on circulating IGF-I, the available data pointing toward local IGF-I are both consistent and compelling. Frystyk concludes by suggesting that it would be prudent to move from the circulation toward skeletal muscle to more completely elucidate the link between exercise, growth factors, and muscle hypertrophy.
In the second paper in these symposium proceedings, Gregory R. Adams, from the University of California, Irvine, a premier researcher who has provided seminal work in the area of IGF-I and skeletal muscle hypertrophy, presents "IGF-I signaling in skeletal muscle and the potential for cytokine interactions" (1). His paper eloquently describes the complex interactions between intracellular signaling pathways of the IGF-I system and proinflammatory cytokines such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and IL-1 within the context of skeletal muscle hypertrophy. The working hypothesis from Adams' laboratory has been that the primary mechanism by which IGF-I contributes to skeletal muscle hypertrophy involves autocrine/paracrine production of IGF-I for the promotion of satellite proliferation and differentiation and subsequent fusion of the differentiated progeny with existing myofibers in support of loading-induced skeletal muscle (2,3). Adams overviews and describes in detail the intracellular signaling pathways and the interplay among IGF-I anabolic signaling and the inhibitory influences of IGF-I signaling via TNF-α, IL-1, and IL-6 (8). TNF-α directly stimulates atrophy in various models and seems to selectively target myosin heavy chain protein. Specifically, TNF-α has been shown to inhibit IGF-I signaling via either nuclear factor κB or c-Jun NH2-terminal kinase by interfering with insulin receptor substrate-1 phosphorylation, resulting in a state of IGF-I resistance and hence negative effects on anabolism (27). IL-1 also has similar effects to TNF-α by interacting with IGF-I signaling via a reduction in the activation of insulin receptor substrate-1 (9). In the context of cytokine/growth factor interactions, alterations in the expression of members of the suppressors of cytokine signaling (SOCS) family can serve as negative regulators of the JAK/STAT signaling pathway (5,28). Specifically, work from Adams' laboratory has demonstrated that chronic exposure to locally elevated IL-6 in rat muscle results in significant increases in SOCS3 mRNA, which have been negatively correlated with myofibrillar protein and also related to IGF-I resistance. A second potential mechanism by which IL-6 might interact with signaling in skeletal muscle involves AMPK, which is known to downregulate protein synthesis via its effects of the mTOR pathway (29). Adams concludes by stating that the cross talk between inflammatory mediators and anabolic processes was an evolutionary useful and adaptive design in helping to protect metabolic processes during times of limited energy resources. Adams also states that additional research is warranted to determine which of the cytokine/anabolic interactions actually takes place in vivo.
In the third and final paper from this symposium, Bradley C. Nindl, of the US Army Research Institute of Environmental Medicine, presents "IGF-I as a biomarker of health, fitness, and training status," in which an overview of selected studies from the literature is provided, supporting the notion that there are associations between IGF-I and several biological end points (e.g., exercise, muscle adaptation, bone and tendon health, body composition alterations, cognitive function, cancer, longevity, and health). Nindl discusses the regulatory complexity of IGF-I by emphasizing that IGF-I biological activity is governed by a family of six different binding proteins and that IGF-I resides in different biocompartments. Nindl further expounds on exercise influences on both circulating/systemic and local IGF-I. It seems that systemic IGF-I may experience biphasic response to exercise training, whereas local IGF-I (IGF-IEa and MGF) experiences a linear up-regulation (12). The fact that circulating IGF-I may actually experience declines with exercise may seem counterintuitive to its known anabolic role, but these reductions occur in the presence of positive neuromuscular adaptations and may rebound and increase with longer training periods. The notion that a critical threshold of circulating IGF-I is important is supported by the double-gene disrupted mice (liver IGF-I-deficient + ALSKO) that have a 90% reduction in circulating IGF-I and show significant impairments in bone health parameters (30).
Within the context of military operational field training paradigms resulting in losses of lean body mass (4,19), Nindl cites research from his laboratory, suggesting that IGF-I has utility as a biomarker in tracking body composition alterations and has prognostic value in predicting fat-free mass losses (18). Data are also presented linking IGF-I with brain and cognitive function. Finally, whereas elevated IGF-I concentrations are considered beneficial in most instances, the paradox that elevated IGF-I is a risk factor for cancer is briefly discussed. Nindl concludes that prospective experimental approaches involving physical activity that can sample and measure IGF-I in the body's various biocompartments (i.e., blood, interstitial fluid, muscle) while using the most biologically relevant assays are encouraged (20,24), as such endeavors will provide greater understanding in the complex role that IGF-I possesses in mediating exercise-induced adaptations.
In summary, each of these papers presents a unique perspective about different aspects of cytokine and IGF-I influences in mediating many of the outcomes of physical activity. When summed in total, the contribution these papers will make will undoubtedly involve bringing attention to the vast regulatory complexity of the IGF-I system and will hopefully convince the reader that the IGF-I system warrants further detailed scientific inquiry to resolve many unanswered questions and paradoxical experimental findings. The IGF-I system remains one of the most intriguing and captivating marvels of human physiology that seems central in mediating numerous adaptations from physical activity.
The results of the present study do not constitute endorsement by American College of Sports Medicine. The opinions or assertions contained herein are the private views of the author(s) and are not to be construed as official or as reflecting the views of the Army or the Department of Defense. Citations of commercial organizations and trade names in this report do not constitute an official Department of the Army endorsement or approval of the products or services of these organizations.
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