INTRODUCTION

TOP ABSTRACT INTRODUCTION WHERE WE ARE HEADED:... FUTURE FUNDING TRENDS AND... FUTURE CHALLENGES IN EXERCISE... WHAT ARE THE HEALTH... CONCLUDING PERSPECTIVES: WORDS... REFERENCES

IN THE PAST 30 YEARS, research involving the acute and chronic effects of exercise (referred to herein as the exercise sciences) has rapidly progressed through various stages. In the late 60s to early 70s, the focus was primarily at the organ level, mainly because of the ability to instrument and monitor both humans and large animals during various exercise paradigms. However, with the introduction of an improved muscle-biopsy technique and the ability to invasively study smaller animals (rodents) during acute and chronic exercise, the focus rapidly shifted to analyses at the cellular and subcellular level. This advancement was facilitated via the use of a variety of evolving biochemical techniques, radioisotope and imaging technologies, which collectively enabled studies of organelle and cellular functions. This stage, which lasted from the early 70s to the mid-80s, was often referred to as the "biochemistry of exercise" era. Then, from the mid-80s to the present, exercise research was transformed even further into what is now termed "the molecular exercise sciences" (2). This latter transformation principally was due to the rapid explosion of various molecular biology tools that have become available to the exercise science community. These include gene-cloning and -sequencing technology, molecular probing via antibodies and oligonucleotides, the use of PCR technology, as well as the development of transgenic and gene knockout animal models. Judging by the recent announcement concerning a call for papers with a molecular/cellular focus on exercise to the Journal of Applied Physiology, there is little doubt that exercise research is currently postured to a greater extent from a molecular/cellular perspective.

These rapid transitions in exercise research have occurred within a single generation of scholars. As we posture for the 21st century and the new millennium, it seems appropriate to pause and examine what the future likely holds for this important scientific discipline. In so doing, the goal of this article is to examine 1) the evolving technologies that are driving scientific inquiry and new discoveries; 2) the funding trends likely to control available resources in a competitive market; 3) the logical knowledge base that must be extended to further our understanding of the molecular and cellular events governing the acute and chronic exercise response; and 4) where we are in terms of enhancing the role of exercise as a key player in the prevention and treatment of those diseases impacting an increasingly aging, sedentary, and culturally diversified society.

As we undertake such an "exercise," the winds of change are already blowing, and the compass is pointing in the direction of integrated biological approaches coupled with the likelihood that the emerging fields of functional genomics and proteomics will become the driving forces dictating new science and research initiatives. Consequently, a key question to be addressed is, How can research in the exercise sciences maintain or even augment its position as a pivotal player in this ongoing scientific revolution?

	WHERE WE ARE HEADED: EMERGING TECHNOLOGIES AND RESEARCH INITIATIVES

TOP ABSTRACT INTRODUCTION WHERE WE ARE HEADED:... FUTURE FUNDING TRENDS AND... FUTURE CHALLENGES IN EXERCISE... WHAT ARE THE HEALTH... CONCLUDING PERSPECTIVES: WORDS... REFERENCES

Human and Animal Genome Projects and Related Technologies

Complementing these remarkable accomplishments in genomic sequencing is the rapidly evolving "gene-chip microarray" technology that will be pivotal in dissecting gene function on a mass scale (7, 10). Miniaturized arrays on microchips are being designed in combination with robotic systems, so that the expression levels for hundreds of thousands of genes can be evaluated simultaneously in a given experiment (7, 10). These technologies (including differential display and subtractive hybridization technologies) will provide "gene-expression profiling" to assess gene-expression patterns in cells and animals and determine changes due to disease and physiological and/or pharmacological interventions. Furthermore, as more expressed sequence tags are defined and linked to specific gene clusters or gene families, the new microarray technology will enable scientists to identify specific sets of genes that are involved with different types of exercise regimens, nutritional profiles, and other environmental factors. Thus this evolving technology will play a major role in providing better insight into the role that exercise might play in affecting the etiology (preventing/ameliorating) of various disease processes as well as that of aging.

To illustrate the power of this new technology, Lee et al. (8) utilized "GeneChip" technology (Affymetrix) to identify ~113 genes likely to be playing a role in the normal aging process and the impact that caloric restriction has in extending the life span of the mouse. This study revealed that ~55 genes were downregulated and that 58 genes were upregulated in old mice maintained on a regular diet; whereas in mice that were caloric restricted by 25% throughout adulthood (a process previously shown to extend the life span of mice by 30%) there was little evidence that the mice experienced these dramatic changes in gene expression. These energy-restricted animals appeared to have undergone what the authors called "metabolic reprogramming." Thus the challenge will be to dissect the genes and functional processes governing this metabolic reprogramming, associated with aging prevention, by using the technologies described below.

Emerging Fields of Research: Functional Genomics and Proteomics

Molecular biology has provided powerful techniques for high-throughput DNA analyses that are not yet reflected in the protein world. This has resulted in an emphasis on the message (mRNA or cDNA) rather than the product of that message, i.e., the protein (1). As most modalities (drugs, exercise, and nutritional interventions) target specific proteins, a route to studying the genome efficiently at the protein level is of great value, and this is what the field of proteomics offers. In essence, proteomics is the study of protein properties (expression level, posttranslational modification, interactions, etc.) on a large scale to obtain a more global view of the physiological processes, disease processes, and cellular-molecular interactions that are defined at the protein level of study (1). Thus this field is considered to be a corollary to the genome-sequencing and/or functional genomics projects, i.e., studying what the functions are of all the proteins and how they interact with one another. Consequently, the field of proteomics will shift a significant component of the science mission back toward a more traditional biochemical/physiological perspective. To gain a more thorough perspective on this field, beyond what can be devoted to in this brief review, the reader is referred to an excellent article on this topic by Blackstock and Weir (1).

	FUTURE FUNDING TRENDS AND RESEARCH PRIORITIES

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As we move to the 21st century, basic and applied research that impacts the exercise sciences will explode on several fronts. This is largely due to the push by both the science community at large and by Congressional leaders to essentially double the research budgets at the National Institutes of Health (NIH; presently at ~16 billion USD) and the National Science Foundation (now at ~3.7 billion USD). As a complement to these proposed budget increases for the two principal agencies supporting biomedical and biological research, the Federation of American Societies For Experimental Biology also has proposed a marked expansion of the research budgets for the US Department of Veterans Affairs, the US Department of Agriculture, the US Department of Energy, and the National Aeronautics and Space Administration, all of which support the initiatives that traditionally have provided research opportunities for individuals focusing on exercise-related research.

Dr. Harold Varmus, Director of the NIH, has released information recently on the Web (see FASEB Newsletter 32: no. 2, 1999; and www.nih.gov/welcome/director/022299.htm) that targets several priorities that potentially could bode well for the exercise sciences. These include areas such as 1) exploiting genomics, i.e., assembling genetic information about the predisposition to diseases, predicting responses to environment, lifestyles (activity patterns), and the design of new therapies; 2) reinvigorating clinical research, i.e., creating new opportunities in the practice of medicine (including sports medicine) at a time when clinical research is perceived to be in a state of decline, by augmenting funding for General Clinical Research Centers (GCRCs). These centers will serve as the backbone for new initiatives in integrated clinical research as well as will translate findings in the basic sciences; 3) harnessing other disciplines and new technologies, i.e., tapping the fields of biology, engineering, and medicine through the development of interdisciplinary programs and centers for drug and molecular development and other initiatives; and 4) eliminating health disparities, i.e., improving living conditions, lifestyles, and general health knowledge and bringing them to all components of our own society and to all nations, particularly as these populations age.

In examining the above initiatives, it is apparent that there are key areas in which the exercise science community could play a pivotal role. For example, in the initiative to expand the role of GCRCs, exercise scientists, in collaboration with their clinical colleagues, should be taking a leadership role in expanding clinically relevant research that needs to be done in order to partition out the effects of exercise in the etiology and treatment of a variety of disease processes such as heart and pulmonary disease, hormonal and metabolic disorders, and musculoskeletal disorders, to name a few (see below).

	FUTURE CHALLENGES IN EXERCISE RESEARCH: BUILDING ON A SOLID FOUNDATION

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In a review appearing in this issue,"Skeletal muscle adaptations to exercise: a century of progress," Hamilton and Booth (6) reported that ~12,000 articles were listed in Medline spanning the last 30 years with the words "muscle," "human," and "exercise" in the abstract. These publications were complemented by an additional ~1,300 papers that included the words "rat" and "treadmill" as descriptors. Due to space limitations, we will use the skeletal muscle system per se as a focal point in bridging the present to the future, because this system is pivotal to the exercise response and to total body homeostasis. Significant strides have been made in recent years in our understanding of the structure, function, and the plasticity (adaptive capacity) of this system (see Ref. 3 for a comprehensive review of the following materials). We know that striated muscle can undergo 1) remodeling of its contractile and calcium-cycling machinery; 2) upregulation of the mitochondrial system; and 3) increases in its capillarity and blood flow/oxygen utilization capacity, in accordance with the increased level of usage imposed on the system. These adaptations collectively contribute to an increase in muscle endurance and a concomitant shift to a more preferential utilization of fat substrate at any given absolute exercise intensity. Depending on the intensity and amount of the applied stimulus, the time frame for these changes can be on the order of days, rather than weeks or months, as previously thought. Also, we know that in response to a high level of mechanical loading (e.g., resistance training), the affected muscles will generate net protein accretion, because their protein synthesis rate exceeds that of protein degradation, i.e., the muscle will enlarge. In contrast, the opposite will occur when the degradation rate exceeds that of synthesis, as occurs during chronic bed rest, in response to spaceflight, and in the sarcopenia associated with aging as well as in diabetes. With the use of a variety of cellular/molecular analytic tools, we know that nearly all the individual fibers comprising either a predominantly slow or a predominantly fast muscle have the genetic capacity for polymorphic expression of the myosin heavy chain gene family and, likely, other gene families (4). However, the extent of such polymorphism depends on the unique combination of stimuli imposed on the muscle fibers. Furthermore, we know that transcriptional mechanisms, coupled to translational events, are operating in the regulation of the many genes that are involved in contractile protein and metabolic enzyme adaptations to exercise (3); and recent investigations have clearly delineated regions of key genes (cis elements) and associated trans acting factors in the regulation of muscle gene expression (9). Thus the field of exercise science clearly has moved extensively in the direction of a cellular, subcellular, and molecular focus. So, where do we go from here?

It is the author's perspective that fundamental, applied, and integrative research that impacts the organ systems associated with a variety of debilitating diseases should be targeted. However, we must first of all focus on more basic issues relevant to exercise physiology. In this review, I will refer to the striated muscle system for illustrative purposes and mention a few key topics to highlight some of the avenues that deserve consideration.

What are the load-sensing components and signaling pathways-regulating processes associated with the compensatory growth (hypertrophy) of muscle fibers? This area includes the involvement of mechanical, hormonal, growth, and neurotrophic factors. Are the proliferation and differentiation processes of satellite cells and other progenitor cells obligatory to the enlargement process? This topic also pertains to fundamental issues related to muscle regeneration from injury/atrophy as well as to the adaptive growth capacity of aged muscles.

What are the transcription and other regulatory mechanisms that coordinate the transformation in fiber typing in response to physical activity and inactivity? Are there concomitant shifts in metabolic profiles that are associated with a given fiber-type transformation, and are these processes coregulated through common signaling pathways?

What is the interplay of activity and hormonal/second-messenger factors in the regulation of the muscle's metabolic and vascular/microvascular remodeling in response to aerobic exercise?

What are the pathways and signaling processes associated with muscle wasting, e.g., protein synthetic/degradation imbalances? Are these imbalances accelerated by aging and corrected by different paradigms of physical activity? Is one type of resistance-training activity, e.g., concentric exercise, more effective than another (isometric exercise) in maintaining muscle mass?

What are the signaling pathways and factors associated with activity regulation of mitochondrial biogenesis? Are there aging-associated defects in the mitochondrial genome that are either exacerbated or improved by activity?

What is the interaction of other systems in the exercise response of muscle? For example, what is the role of the immune system and its related components (cytokines, macrophages, etc.) in the acute and adaptive response of the muscle system to exercise?

The above questions by no means adequately cover the field of muscle biology as it applies to future research in the exercise sciences, but they serve as logical examples of the evolution of research topics that need to be addressed based on the exciting findings that have been provided to date, mainly in the last two decades. These areas should serve as a logical foundation on which to base more general and applied questions that relate the importance of physical activity and inactivity to the health concerns of our society.

	WHAT ARE THE HEALTH CHALLENGES OF TOMORROW AND WHERE DOES EXERCISE SCIENCE FIT?

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Despite the great strides that have been made to improve one's general health and to increase the longevity of the populace, there are many challenges that remain to be addressed. While significant inroads have been made in the last 25 years to reduce the number of heart attacks, success in this area has been tempered by the marked increase in the number of individuals diagnosed with congestive heart failure and other cardiovascular disorders. Due to the nature of these disorders and the present treatment technologies readily available, heart transplantation appears to be the primary and possibly the only adequate treatment strategy currently available. Metabolic-related diseases associated with obesity and type II diabetes are reported to be at an epidemic level (2). And while we have extended the life expectancy significantly, it remains to be seen what the quality and productivity of this life extension will be, given the number of aged individuals suffering from musculoskeletal disorders (osteoporosis and sarcopenia) and/or frailty that have resulted in increased morbidity and mortality.

In each of these settings, a sedentary lifestyle and/or insufficient aerobic and resistance-loading activities have been proposed to be critical components to the risk factors affecting these degenerative processes. Thus significant challenges remain. With the completion of the human genome project, a major task will be to identify which genes are associated with a given disorder and whether lifestyles (activity and nutrition patterns) affect the expression of these genes. Consequently, an integral component to understanding the genetic basis of a given disorder will be whether some form of an exercise prescription, by virtue of its impact on the expression of various genes, can be used effectively in either the prevention or treatment of a given disorder. As noted above, this will require an integrative perspective, using the technology evolving from the fields of functional genomics and proteomics as well as basic and applied exercise research, involving a variety of animal and cell model systems, thereby culminating in the translation of information to the human research setting involving the GCRCs. Examples of the role of the GCRCs in the diagnosis and treatment of various diseases are illustrated below.

Increased research is needed to learn about the interaction of physical activity and chronic disease at both the fundamental and cultural (lifestyle) and behavioral levels. How does physical activity affect the aging process, and does inactivity accelerate it? Is physical activity protective to bone and muscle conservation throughout life?

Physical activity increases insulin sensitivity and thus may be beneficial in preventing type II diabetes. Epidemiological studies have demonstrated that individuals who are physically active have a much lower risk of developing type II diabetes. What is the mechanism of this association? Can exercise paradigms, in combination with nutritional and pharmacological approaches, effectively eliminate this disease?

Obesity is thought to be caused by either an excess of caloric intake, insufficient physical activity, or a combination of the two. Whereas certain genes impacting hormonal processes likely make one more susceptible to being overweight, there appear to be "lifestyle triggers" to the problem. Several organ systems such as adipose, brain, liver, pancreas, and skeletal muscle appear to contribute to the onset of both obesity and diabetes, but little is known as to how physical inactivity affects each of these systems in the etiology and treatment of these disorders. Thus it would appear that an integrative research perspective needs to be established in addressing these complex disorders, with exercise as a central focus.

	CONCLUDING PERSPECTIVES: WORDS OF CAUTION

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There remains a tremendous challenge to solving the health problems impacting the future of mankind that can only be achieved by an integrative research approach spanning many disciplines and technologies. As such, it is increasingly apparent that individuals involved in either the basic or applied disciplines of exercise science have unique expertise and the technical capabilities that can contribute to solving these many scientific and health-related problems. It is time to amalgamate the expertise and technology within the field of exercise science and carve out a place for it in the next century of biomedical research and health care prevention and treatment. To accomplish this, two critically important issues need to be addressed. First, academic programs committed to educating future exercise scientists need to develop broader training programs covering pertinent subject matter and laboratory training that spans molecular biology through integrative systems physiology to better link the two spectrums in scientific inquiry. Second, the community of exercise scientists must provide a stronger voice to the NIH (and other funding agencies) to ensure that the scientific discipline that we call "exercise science" is not lost in the reconfiguration process that is taking place at the NIH's Center For Scientific Review. As it stands now, the proposed configuration of the future study section infrastructure does not bode well for the review of grant proposals pertaining to exercise science topics. Thus, if these latter issues are not appropriately addressed, the future of exercise science in the next century could go the way of the dinosaur.