In Memoriam

Abstract

On August 25, 2013, the exercise science world lost a true leader and visionary with the passing of Dr. Priscilla Clarkson, renowned scientist, Distinguished Professor, Dean, and celebrated mentor. Dr. Clarkson crafted an exquisite legacy of groundbreaking research in muscle function while touching the lives of countless colleagues, mentees, and friends along the way. We, the co-authors of this article, represent a small number of the many people she trained over a 30+ year career at the University of Massachusetts, Amherst. We remember Dr. Clarkson for the innumerable life lessons that she taught us, from commitment to community and collaboration, to the joys of teaching and helping others. This memorial article is a chronicle of achievement, a remembrance and tribute, and a heartfelt “thank you” to a woman who gave us so much and changed our lives. Early Influences and Passions Priscilla Clarkson (nee Massei) was born, raised, educated, and lived her full life in the state of Massachusetts. A native of Worcester, Priscilla grew up with several passions that lasted throughout her lifetime, including loves of classical ballet, the outdoors, and animals. As a lifelong investigator of science and aficionado of classical ballet, Priscilla's unparalleled professional and personal achievements blended a scholar's quest for knowledge with a ballerina's precision in execution. She served at various times as president, board member, and choreographer-in-residence for the Pioneer Valley Ballet ensemble in Easthampton, MA, for which she performed annually in the role of the mother in “The Nutcracker” for many years (Figure 1). She combined her loves of dance and science in the books she authored, including Dancing Longer, Dancing Stronger: A Dancer's Guide to Improving Technique and Preventing Injury (1990) and Science of Dance Training (1988).Figure 1: Priscilla during her years performing with the Pioneer Valley Ballet (circa 1992).Figure 2: Dr. Clarkson as outgoing president of ACSM in 2000.Figure 3: Dr. Clarkson at 2010 ACSM Conference Honor Award Ceremony with former UMASS students. (From left: Eric Rawson, Sandy Hsieh, Cynthia Chi, Adam Persky, Melissa Roti, Mary Miles, Priscilla Clarkson, Maria Urso, Monica Hubal, Amy Kearns, and Kimberly Reich).Another defining passion throughout her life was her tremendous love and compassion for animals. Priscilla was a protector and rescuer of animals in need. Her house was always filled with cats and dogs that were loved and cared for immensely. They roamed through her house and beautiful gardens. At the many gatherings that she and her husband Ron Pipkin hosted in their home, guests could always expect a cat or dog to share a couch or chair with them. Priscilla and Ron were great partners who shared interests, travels, love of reading, their animal family, and many laughs over decades of marriage. Professional Accomplishments University of Massachusetts Priscilla Clarkson spent her entire academic career at the University of Massachusetts, starting as an 18-year-old Zoology student in 1965 and culminating in her role as Distinguished University Professor and Dean of the Commonwealth Honors College in 2006. She sequentially earned her bachelor's degree in Zoology in 1969, master's degree in Marine Science and Zoology in 1973, and doctoral degree in Exercise Science and Human Movement in 1977. Immediately upon graduating, she began her teaching career as an Assistant Professor in the Department of Exercise Science. In her 48 years at UMass Amherst, as a student and professor, Dr. Clarkson authored more than 200 scientific publications, mentored 13 doctoral students and 5 postdoctoral fellows, and was awarded millions of dollars in external research support from prestigious institutions such as the National Institutes of Health, Christopher Reeve Foundation, Department of Defense, Medinova, Inc., Quaker Oats Company, Proctor and Gamble, and Whitehall Laboratories. In light of her national renown, her academic home recognized their star. The campus awarded its two highest honors to Dr. Clarkson—the Chancellor's Medal in 1997 and the title of Distinguished Professor of Kinesiology in 2008. Reaching the top of her field destined Dr. Clarkson to further inspire students. She was appointed dean of Commonwealth Honors College in 2006, where mentoring talented students was her top priority. On accepting the appointment she said, “I look forward to working with Commonwealth College's first-rate staff and faculty to create a new vision that will attract academically talented students from all backgrounds. It is an exciting opportunity to help these highly motivated students develop the scholarship, creativity, citizenship and leadership skills necessary to address the complex problems of society.” She led the way for the creation of an innovative housing/learning Honors College complex, whose 6 new buildings have helped transform the campus. American College of Sports Medicine Dr. Clarkson found a second family and home within the American College of Sports Medicine (ACSM) community. She served ACSM in an extraordinary number of capacities at the regional and national levels: as a committee member, chair, moderator, position stand/roundtable author, speaker, fellow, board member, as Editor-in-chief of Exercise and Sports Science Reviews, President of New England ACSM, and as President of the National ACSM (2000; Figure 2). Her tireless dedication to the College was rewarded with the Citation Award (1997) and the ACSM's most prestigious recognition, the Honor Award (2005). In 2007, Dr. Clarkson delivered the Joseph B. Wolffe Memorial Lecture at the American College of Sports Medicine's annual meeting (New Orleans, LA). Her presentation, appropriately titled, “Muscle Soreness: Cause, Consequence and Cure” represented a culmination of her many discoveries in skeletal muscle research. An achievement that is difficult to capture in print was the extent to which Dr. Clarkson was known for her engaging personality and consideration for others within the organization. As described by Robert Sallis (ACSM past president), “I have met a lot of brilliant people during my career, but few on her level. She could talk to anyone about anything and provide incredible perspective and guidance. She was also exceedingly kind and always willing to help, whether it was to review a paper, collaborate on symposia or provide advice on career choices, she was always willing and able to help.” The dedication to professional service that Dr. Clarkson inspired in her students and mentees will be an enduring tribute to a leader who considered service as a responsibility and honor. Research Career Dr. Priscilla Clarkson's many legacies include her work as a modern pioneer in the study of muscle damage and an expert in the field of sports nutrition. However, her research career spanned a range of topics, all under the umbrella of muscle function and adaptation to challenge. Her work encompassed over 30 years of study with early work in motor control and muscle physiology, leading into decades of work on how skeletal muscle is affected by strenuous exercise. This later work evolved to keep up with the changing landscape of research. As an expert in skeletal muscle function and response to exercise, she was approached in the late 1990s to be a coinvestigator in a large study investigating genetic influences on skeletal muscle size and function. Based largely on the work in that study, Dr. Clarkson morphed her laboratory from a largely functional testing laboratory into one that studied molecular biology and genetic influences on muscle. Overall, her work and insights will provide future investigators an extensive knowledge base from which to elaborate for discoveries in both basic and applied research in muscle and exercise physiology. We summarize here some key elements of her research career. Early Career—Motor Control Research The foundation for Dr. Clarkson's research career in muscle physiology and metabolism came from her doctoral training and early research in the area of motor control. She investigated the influence of age, physical activity, muscle fiber type, exercise training, and fatigue on motor control elements such as fractionated reaction time (premotor and motor times), response time, and force development (9,10). These were very productive early years in which her research findings revealed a puzzling phenomenon of prolonged fatigue that coincided with an increase in the activity of an intramuscular enzyme, creatine kinase (CK), in the circulation (13). This finding led to the early conclusion that “mechanical factors associated with high tension levels may be responsible for CK efflux following isometric exercise” (13), one of the first, if not the first, papers relating increases in serum CK activity to the tension/stress placed on skeletal muscle during strenuous exercise. Prior to this seminal paper, researchers had primarily identified skeletal muscle efflux of serum CK as a consequence of excessive alcohol consumption, poisoning, surgical trauma, vitamin E deficiency, or myopathies such as Duchenne muscular dystrophy. Exercise-Induced Muscle Damage and Adaptation—Part 1 Stemming from her early findings, Dr. Clarkson earned a strong reputation as an innovative leader in understanding how skeletal muscle responds to strenuous exercise, furthering her earlier findings of CK leakage into circulation. This included the standardization of laboratory methods to create exercise-induced muscle damage (EIMD) that was robust enough to track its typical development and resolution (3,7,11,15,17,33), but not so severe that it caused clinically significant damage in healthy subjects. This was accomplished by having volunteers perform eccentric contraction-biased exercises, as lengthening contractions are known to cause EIMD. Dr. Clarkson's body of work on muscle damage had early foci in functional adaptations to novel exercise (16,32) and how extreme cases of muscle damage can be manifested as clinically-relevant rhabdomyolysis (6,8,20,41). Dr. Clarkson was a pioneer in the identification of the phenomenon known now as the “repeated bout effect”, in which performance of a bout of eccentric exercise attenuates the damage expected to be seen after performing a subsequent bout of the same exercise (2,11,14,16,32). In one of the first studies published on this topic, Dr. Clarkson et al. (14) observed a blunting of the serum CK response to a second bout of similar exercise performed 1 week after the initial bout. Interestingly, this reduction was not due to any differences in tension levels between the 2 bouts, suggesting that the initial bout did not damage the muscle to a greater degree and thus explain the observed difference. A blunting of serum CK activity was not the only metric that changed in this paradigm. Dr. Clarkson's work showed that when subjects performed repeated bouts of eccentric exercise even up to 6–10 weeks apart, there were smaller changes in muscle soreness, range of motion, and strength loss following the second bout (32). Moreover, the protective effect of an initial bout of exercise was still present up to 6 months after the original bout. Overall, this early research was critical to the field, not only from the standpoint of the discovery and exploration of a unique skeletal muscle phenomenon, but because it exposed a fatal flaw in earlier research designs examining the effects of analgesics on muscle pain. In these studies, the natural differences in pain response after 2 similar bouts of exercise to induce muscle pain may have been erroneously attributed to the presence of an analgesic. Dr. Clarkson revisited the phenomenon of the repeated bout effect later in her career, as well, exploring at length the molecular underpinnings of adaptation, which we describe in greater detail later in this review. One of Dr. Clarkson's major interests exploring skeletal muscle damage was rhabdomyolysis, the rare but extreme form of muscle damage resulting from unaccustomed, overexertion exercise. Dr. Clarkson used upper extremity eccentric exercise as a model in which to study this phenomenon because it typically induced a mild form of rhabdomyolysis (i.e., resolved normally within days without complications in healthy subjects). However, Dr. Clarkson also observed that a small percentage of research volunteers (3–5%) showed some extreme changes in the major indices of muscle damage after undergoing this exercise. She described the “high responder” to eccentric exercise in a case study of 6 individuals who demonstrated profound and prolonged losses of strength (lasting several months), extreme muscle soreness, impaired range of motion, and profound increases in CK activity and myoglobin in the blood after eccentric exercise (43). This work was the first to show the potential dangers associated with eccentric exercise; moreover, Dr. Clarkson was instrumental in educating the scientific community about this phenomenon, insisting that laboratories performing eccentric exercise protocols be aware of these responses. Dr. Clarkson was a keen advocate of human subjects protection and served as the head of the UMass Amherst Internal Review Board for many years. Her work on rhabdomyolysis helped prepare others in the field to recognize the signs and symptoms of the disorder, outlined strategies for minimizing adverse events to protect research participants, and created a safer environment when conducting this type of research (41). The observation of the “high responder” to eccentric exercise sparked an interest in Dr. Clarkson to find out why there was such great inter-subject variability in the muscle damage response among individuals performing a standardized exercise protocol. Her work continued to document prolonged and profound muscle damage in high responders (40) as well as the potential neuromuscular mechanisms responsible for high responses to eccentric exercise (42). As with the repeated bout effect, later work expanded on this work by searching for mechanisms at the molecular level for inter-subject variability (summarized later in this review). Sports Nutrition and Muscle Function While pursuing her seminal studies in muscle damage, Dr. Clarkson also began research in corresponding areas related to muscle health. When presented with the opportunity via colleagues within ACSM, Dr. Clarkson started to explore the interactions between nutrition and skeletal muscle function. Between 1990 and the early 2000s, her nutrition research generated more than 100 professional presentations and more than 60 publications. In particular, her work in antioxidants, mineral metabolism, and later with the dietary supplements chromium picolinate and creatine monohydrate helped push the young field of sport nutrition into the 21st century. A lasting effect of this work was an elevation of the quality and impact of dietary supplement research. In particular, Dr. Clarkson's investigations into the effects of creatine monohydrate supplementation in older men (36,37) opened the door for mechanistic and applied research on the potential benefits of myotrophic supplements in older adults and patient populations. Dr. Clarkson's service to the sport nutrition and exercise metabolism research community was profound. She served on the Committee on Military Nutrition at the Institute of Medicine, on the Gatorade Sports Science Institute Sports Medicine Review Board, and as Editor in Chief of the International Journal of Sport Nutrition and Exercise Metabolism (8 years). Her tenure on the National Collegiate Athletic Association (NCAA) Competitive and Medical Safeguards Committee (1997–2001) coincided with the death of three collegiate wrestlers, and Dr. Clarkson was an important voice in discussions about the development of minimal weight standards and dietary supplement use among collegiate athletes. Dr. Clarkson's expertise was often requested as an author of “roundtables” and position stands (4,12). These publications in particular show the impact she had on summarizing the research and establishing best practices for the area. Exercise-Induced Muscle Damage and Adaptation—Part 2 Since the early 1980s, Dr. Clarkson published extensively about the physiological responses to eccentric exercise, but it was still not known why eccentric exercise caused skeletal muscle soreness or why the repeated bout occurred, or why there was such a variable response in muscle damage markers in the blood. The limitations of her previous work, as she described, were that she could not characterize what the cell was “thinking.” In other words, how were genes signaling skeletal muscle after eccentric exercise to initiate changes in skeletal muscle proteins to promote repair and adaptation? This information would lend clues into the pathways that may regulate pain, soreness, regeneration, and ultimately, hypertrophic muscle responses. The completion of the Human Genome Project at the turn of the century brought exciting new opportunities to explore muscle damage at the genetic and molecular levels, and Dr. Clarkson was never one to let new opportunities pass by. In 1999, Dr. Clarkson began a working collaboration with 2 key external investigators, Drs. Eric Hoffman and Paul Thompson, as part of the Functional Single Nucleotide Polymorphisms Associated with Muscle Size and Strength (FAMuSS) Study (46). Work with Dr. Hoffman's group enabled Dr. Clarkson to leverage new technologies such as gene expression profiling to gain new insight into muscle's response to exercise induced muscle damage. In the first paper from this collaborative group (which would go on to publish more than 30 additional papers, as well as several review articles and book chapters), Dr. Clarkson characterized the transcriptional response of skeletal muscle to eccentric exercise in humans (5), representing a preliminary step in understanding the molecular processes that regulate skeletal muscle remodeling, specifically those related to inflammatory responses after eccentric exercise. The success of this early project motivated Dr. Clarkson to pursue more mechanistic studies to understand the regulatory mechanisms that mediate muscle adaptation and pathogenesis. While the study of human subjects was essential for defining the “real world” problem, they were not ideal for some basic mechanistic studies. As she was philosophically opposed to the use of animals in research, to solve this problem Dr. Clarkson turned her attention to the use of mammalian myoblast cultures. In 2000, Dr. Clarkson undertook a sabbatical in the laboratory of her UMass Amherst Colleague, Lawrence Schwartz (Department of Biology). She and her students continued to collaborate with the Schwartz laboratory for the rest of her career (27,28). Dr. Schwartz observed “Priscilla's work always started with a real world clinical observation or problem and then quickly developed into a focused, hypothesis driven molecular and cellular study. One of the things I really admired about her as a scientist was that she was fearless about bringing new technology to the lab and to the field. She was always at the cutting edge of her discipline.” Over the next 10 years, Dr. Clarkson published over 75 peer-reviewed papers on topics ranging from muscle damage (5) and adaptation (23) mechanisms to molecular profiling of statin-induced myopathy (26,48) or spinal cord injury (50). Her original transcriptomic study that described a complex inflammatory response to novel eccentric exercise was followed by work highlighting the role of monocyte chemoattractant protein 1 and other related genes with the repeated bout effect (23). Later work from her laboratory group specifically examined the role of vascular changes in muscle following eccentric exercise, finding activation of an important inflammatory modulator (nuclear factor-kappa B) surrounding pericytes (specialized cells surrounding blood vessels that play regulatory and stabilization roles in muscle) (29). Revisiting Dr. Clarkson's earlier focus on the intersubject variability present in the muscle damage and adaptation responses, she began exploring the potential genetic and molecular mechanisms driving this variability. While some investigators are uncomfortable with subject variability, Dr. Clarkson dedicated much of her career dissecting the potential mechanisms responsible for it. As a direct result of her involvement in the FAMUSS study, one focus of her laboratory was to identify specific single nucleotide polymorphisms that may predispose how an individual responds to eccentric exercise (18,19,21,22,25,46). Aside from her own desire to answer a specific scientific question, Dr. Clarkson was well aware of the implications of these data in unique populations such as military personnel and others who may be predisposed to clinically-relevant rhabdomyolysis. This research was the start of collaborative efforts with the military and local police and fire training academies. One of the most important concepts that Dr. Clarkson uncovered with these efforts was stressing the need for larger-scale studies that evaluated many genes, not just a single gene that an investigator chose a priori. While she only just began to uncover the complex interactions in gene signaling associated with skeletal muscle damage, her work has had a dramatic influence on how recruits are trained. Another research topic that aligned with her interest in exercise-induced rhabdomyolysis and unique scenarios that would predispose an individual to extreme responses was statin-induced myalgia. Intrigued by the high number of reports of muscle pain with statin medications, she sought the opportunity to understand how skeletal muscle is altered when an eccentric bout of exercise is performed while taking high or low dose statin medications (1,20,26,30,35,44,47,48,52). Although her work did not provide a definitive conclusion before her passing, she put forth several theories, including attributing maladaptations to transcriptional deficits in energy producing machinery within skeletal muscle cells (26). Dr. Clarkson's critical work in this area has helped elucidate the mechanisms behind statin-induced myopathy and has set the stage for future researchers to explore questions surrounding predispositions to myopathy and rhabdomyolysis. In addition to her work on damage and myalgia, Dr. Clarkson worked closely with the Christopher Reeves Foundation. Part of this work was designed to understand the molecular mechanisms that mediate skeletal muscle atrophy in response to spinal cord injury or prolonged periods of unloading or disuse. Her goal was to develop tools to help in the identification of potential pharmacological targets to attenuate skeletal muscle atrophy in inured, diseased and elderly populations (39,49,50). Her work identified specific components of the ubiquitin proteasome pathway that are differentially expressed during the first few hours following unloading or spinal cord injury. This information has been, and continues to be, landmark data for scientists exploring the molecular aspects of skeletal muscle atrophy. National Strength and Conditioning Association As a keen scientist who always kept the applications of her discoveries in sight regardless of the intricate mechanisms being examined, Dr. Clarkson's research set the quintessential example of “bridging the gap between science and practice”—the mission of what the NSCA stands for. Dr. Clarkson was a strong advocate for the NSCA in its early years, providing scientific evidence and scholastic credibility to an organization founded originally on athletic applications. As noted by Dr William J. Kraemer, Editor-In-Chief of the journal who stated: “I had the honor to meet Dr Clarkson at an ACSM meeting in 1977 and ten years later when I asked her as a friend, if she would help us launch this new applied sports science journal, after an explanation of what it was all about, without hesitation she was on board. I cannot tell you that in those early days and months of the JSCR in 1987, it was so important to have her name associated and involved with this new journal launch. Even then, her charisma, reputation, knowledge, and enthusiasm for whatever she did were absolutely infective and the JSCR benefited immensely. She was a friend who was not afraid to put her reputation on the line in support of the journal when many doubted such a journal was even needed.” It was her discreet leadership and persistent advocacy that helped successfully guide the NSCA to fulfilling its mission. During her guidance, Dr. Clarkson served as one of the first associate editors of The Journal of Strength and Conditioning Research helping to put practical sports science into the hands of coaches and athletes. Among her contributions to the science underlying practice, Dr. Clarkson published some seminal studies in The Journal of Strength and Conditioning Research on mechanisms of resistance training and the effects of creatine supplementation on exercise-induced muscle damage (24,38,45). She even published a highly practical case study of exertional rhabdomyolysis in a healthy collegiate football player in 2009 (31), educating the athletic community on the dangers. Among her most recent contributions to the journal were her insights into genetic variants in muscle performance published in 2012 (51). While, not all of us were lucky enough to have the chance to personally know her, watch her, or listen to her, all of us share in the gifts of Dr. Clarkson's many important contributions. We all owe Dr. Clarkson a great debt to her for helping us to understand muscle function and soreness—practical science that coaches and athletes apply each day. Legacy Dr. Clarkson's range of work over 30 + years impacted a tremendous number of people. She traveled all over the country and the world, delivering keynote lectures at international conferences as often as she presented at ACSM regional conferences, at undergraduate colleges, and in the community. She treated each trip, whether near or far, as an opportunity to meet new people, especially in the exercise science community. Her articles were equally as far reaching, and appeared in applied publications, basic research journals, and books. Her prolific work was also highly cited, with over 7000 citations of her work in over 5000 scholarly articles. Priscilla Clarkson was known for her incisive mind and astute creativity as well as her research and professional contributions, but her legacy certainly includes a great many people whose lives and careers she influenced. For example, Kazunori (Ken) Nosaka spent 2 years working in Dr. Clarkson's lab as a visiting scientist and remarked that “These two years changed my life, and without Priscilla, I would not have been passionate about the muscle damage research that I have been doing for more than 20 years, and that I consider to be my life work.” Stella Volpe notes, “When I was a junior faculty member, Priscilla took me under her wing, to guide and promote me. She told me, ‘Do the research you want to do, and not what others think you should do.” Her power as an educator was always rooted in her passion for learning. Barry Braun (former master's student) notes “What made Dr. Clarkson a highly effective educator was that she never ceased to be a student. She refused to sequester herself in a zone of intellectual comfort and teach from the safe bunker of what she already knew. She actively sought out new intellectual challenges and was not afraid to know less than the ‘experts’ in a particular area new to her.” Dr. Clarkson will forever be remembered as an inspiration and a mentor. She developed the passions and productivity of her colleagues, collaborators and students. Monica Hubal (former doctoral student) notes “She challenged all around her to perform at their best, and she never gave anything less than her best in return. I worked with her for almost 15 years as a student and then collaborator and I never once waited on her to get anything back to me. I spent the whole time trying to get her results fast enough!” She also had clever ways of making her points, e.g., “She would draw a circle on the board and say everything in the circle is what you know, everything outside the circle is what you don't know and the perimeter of the circle is what you know you don't know. Then she drew a bigger circle to show that when you know more, you also know that there is more you don't know,” reminisces Melissa Roti (former master's student). Steve Sayers (former doctoral student) adds “I know many of Dr. Clarkson's students and colleagues have latched onto some “Priscilla-isms” and use them as mantras in their careers and lives. One of my fondest is the phrase, “Once started, half done” which has served as a great motivator throughout my career.” Although Priscilla's professional successes were innumerable and her contributions enduring, it was her brilliant character that was so captivating. She was incredibly funny and loved to laugh. She had a wonderful smile and always made the person she was talking to feel respected and appreciated. She was never self-promotional (longtime collaborator Eric Hoffman referred to her as “highly other-centered”) and felt some discomfort with the awards and honors that the field bestowed upon her, but was always overjoyed at the successes of her students. She continued her work until just a few weeks before her passing, committed to be of use to her beloved communities. Priscilla left us with a legacy of scientific achievement, eloquent insights, leadership accomplishments, a host of students and colleagues made better by all that she gave, and an even greater number of people touched by the enormity of her heart. She inspired so many of us to want to achieve, to do it with integrity, and to help others. ACSM past president Charlotte “Toby” Tate notes, “Although Priscilla is gone from this world, her light continues on in the people and animals that were fortunate to have known her. She is missed.” Acknowledgments We, the co-authors of this article, proudly represent only a small number of the many whom Dr. Priscilla Clarkson mentored during her career. We would like to acknowledge the many friends, students, and colleagues whose lives were changed by Dr. Clarkson's influence, especially those who provided personal testimonials and quotations for this memoriam. Additionally, we would like to especially acknowledge those in the Department of Kinesiology (formerly the Department of Exercise Science) and Muscle Biology Laboratory at the University of Massachusetts whose friendship, collaboration and hard work over the years contributed to the Clarkson legacy. Finally, we gratefully acknowledge Priscilla's husband, Ron Pipkin, and the American College of Sports Medicine for granting permission to use photos in this memoriam.