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Genetic determinants of exercise training responses

Michael Massett, Ph.D.

Assistant Professor

Low exercise capacity or cardiorespiratory fitness is comparable to elevated systolic blood pressure, obesity, diabetes, and smoking as a risk factor and predictor of future disease.  However, there is a high degree of individual variation in cardiorespiratory fitness before and after exercise training, including individuals that may not respond at all to training. Non-responding individuals might not benefit from increased physical activity and may be at higher risk for diseases related to low fitness, such as cardiovascular disease, metabolic syndrome, and breast and colon cancer. The genetic factors determining the magnitude of the response to exercise are poorly understood. Therefore, the objective of this research is to use genetic/genomic approaches including quantitative trait loci (QTL) mapping to identify novel candidate genes that influence the variation in exercise training responses.  Using QTL mapping, potential QTL for exercise-training responses have been identified on chromosomes 2, 12, and 14 (LOD 3.49 – 6.25). These data suggest that variation in the responses to exercise training (trainability) is affected by specific chromosomal regions and likely specific genes. Genetic and bioinformatics approaches will be used to identify and narrow QTL that affect variation in exercise training adaptations based on changes in exercise performance. Congenic strains of mice will be created to confirm and narrow the QTL intervals.  Finally, candidate genes will be identified using microarray analysis. Overall, these experiments will provide insight into the genetic basis for individual differences in the responses to exercise training as well as identify novel candidate genes that determine these individual differences. Because improving cardiorespiratory fitness through exercise training can significantly reduce the risk of cardiovascular disease, metabolic syndrome, and breast and colon cancer, understanding the genetic factors associated with the variability in the adaptation to exercise training may help to elucidate the mechanistic basis for chronic diseases associated with low levels of fitness.


Egg Cholesterol Consumption, Blood Cholesterol and Skeletal Muscle Hypertrophy

Steven E. Riechman, Ph.D., M.P.H.

Assistant Professor

The primary objective of this study is to have 36 men and women (age 50-69) perform 12 weeks of resistance exercise training for the purpose of inducing skeletal muscle hypertrophy.  These individuals will consume either 0, 1, or 3 whole eggs per day in a double-blind design to test the hypothesis that dietary cholesterol is essential for skeletal muscle hypertrophy.  If so proven, this will confirm a very strong association between dietary cholesterol and hypertrophy observed in a previous study of 51 men and women (age 60-69). The current proposal is using a randomized double-blind, placebo controlled design to provide the most conclusive evidence that dietary cholesterol plays an essential role in skeletal muscle hypertrophy. The secondary objective of this proposal is to test the hypothesis that increased dietary cholesterol consumption in the context of an exercise program does not alter blood cholesterol concentrations or cardiovascular risk.


Exercise Protects Heart Cells from Apoptosis and Death in the Aging Heart

Dr. John M. Lawler, Ph.D.

Associate Professor

Aging is characterized by a progressive reduction in contractility and maximal cardiac output along with an increased risk of morbidity and mortality from cardiovascular diseases. One critical factor that contributes to age-related decline in cardiac function is the loss of cardiac myocytes. Indeed, the typical 70 year old man will have a 30% reduction in the number of myocytes. This has important clinical relevance as the heart cannot easily replace lost cells. Myocytes may be lost through necrosis or programmed cell death termed “apoptosis.” A 200% increase in cell death with aging without signs of necrosis. Recent evidence also indicates elevated pro-apoptotic signaling in the aging heart. An important target of aging may be the mitochondrial Bcl-2 family (e.g., Bax, Bad, Bcl-2) pathway and caspase-3 activation. In contrast, endurance exercise training consistently improves cardiovascular function and reduces risk of morbidity and mortality from cardiovascular diseases. However, the mechanisms by which exercise training may spare loss of myocytes and cardiovascular function with increasing age are unknown. Our goal is to determine the mechanisms of exercise protection against pro-apoptotic signaling in the aging heart. Specifically, we will test the hypotheses that (a) exercise training will ameliorate age-induced increases mitochondrial Bcl-2-family driven apoptosis in the rat left ventricle and (b) exercise training will partially protect against doxorubicin-induced increases in apoptosis in the aging left ventricle. Four (young adult) and 24 month old (old) Fischer-344 rats will be divided into sedentary and exercise trained groups. Exercise training regiment will be 12 weeks long using uphill treadmill running. The left ventricle will be analyzed for Bcl-2 family, caspases, and DNA fragmentation/apoptosis using Western immunoblotting, ELISA techniques, and immunohistochemistry techniques. Mitochondrial respiration will also be assessed. We expect that exercise training will attenuate age-induced increases in apoptosis in the heart. We further expect that the results from our investigation will directly lead to new therapeutics combining exercise training with targeted pharmaceuticals that will relieve the decline in heart function by aging.

Sponsors: Texas Affiliate of the American Heart Association, Texas A&M Vice President's Office for Research.
Initial Publications and abstracts:


Kwak, H.-B., W. Song,, and J.M. Lawler. (2006). Exercise-training ameliorates age-induced elevation in Bcl-2 family pro-apoptotic signaling in the aging rat heart. The FASEB Journal. In Press.

Lawler, J.M., H.B. Kwak, and J.H. Kim. Twelve weeks of exercise training upregulates Mn-SOD while reducing iNOS and oxidative stress in the rat left ventricle. 2006 American College of Sports Medicine meeting, Denver, CO. Med. Sci Sports Exer. (abstract) In Press.


Kwak, H.B., W. Song., J.H. Kim, and J.M. Lawler. Responses of fas/cytokine-mediated apoptotic pathway to 12 weeks of treadmill training in the aging rat heart. Experimental Biology ‘06 meeting, FASEB J. In Press.

Kwak, H.B., W. Song, and J.M. Lawler. Exercise training ameliorates age-induced elevation of caspase-9, cleaved caspase-3, and apoptosis in the rat heart. Paper presented at the International Union of Physiological Sciences/Experimental Biology 2005 meeting in San Diego, CA. FASEB J. 19: A1569, 2005.


Project:  Vascular Biology: Aging and Endothelial Dysfunction

Dr. Christopher R. Woodman, Ph.D.

Assistant Professor

The general aim of this research project is to determine the interactive effects of aging and exercise on skeletal muscle vascular beds.    The primary goal is to understand the mechanisms by which endothelial and vascular smooth muscle cells adapt to aging resulting in increased risk of developing cardiovascular disease.  In addition, we study mechanisms by which exercise training attenuates or reverses the detrimental effects of aging on vascular cell function.  Functional studies are conducted using isolated perfused arteries to determine the cell signaling events in endothelial and vascular smooth muscle cells that mediate endothelium dependent vasodilation.  Biochemical and molecular techniques are used to determine mechanisms contributing to age-induced endothelial dysfunction and to determine mechanisms by which exercise training improves vascular cell function in senescent arteries.

Sponsors:  National Institute on Aging

  

Selected Publications:

Woodman CR, Price EM, and Laughlin MH.  Aging induces muscle specific impairment of endothelium-dependent dilation in skeletal muscle feed arteries. J Appl Physiol 93: 1685-1690, 2002.

Woodman CR, Price EM, and Laughlin MH.  Aging impairs nitric oxide- and prostacyclin-mediation of endothelium-dependent dilation in soleus feed arteries. J Appl Physiol 95: 2164-2170, 2003.

Laughlin MH, Woodman CR, Schrage WG, Gute D, and Price EM.  Interval sprint training enhances endothelial function in some arteries that perfuse white gastrocnemius muscle.  J Appl Physiol 96: 233-244, 2004.

Woodman CR, Price EM, and Laughlin MH.  Shear stress induces eNOS mRNA expression and improves endothelium-dependent dilation in senescent soleus feed arteries.  J Appl Physiol 98: 940-946, 2005.


 

Program Evaluation: The Unsung Challenge

 

Dr. B.E. Pruitt, Dr. Patricia Goodson, along with doctoral students Sandy Suther and Kelly Wilson are wrapping up the second year of their evaluation of the abstinence-only-until-marriage programs in the state of Texas. These programs are designed to teach youth about the benefits of abstaining from sexual activity until marriage; they are funded by Title V federal grants to the states. During these two years, evaluation efforts have centered on implementation issues: the obstacles that these programs face, staff's perceptions of how/why these programs work, and how programs are managed on a daily basis. Recently, author Michael Erard interviewed Dr. Goodson and Dr. Pruitt about their evaluation. Erard's view of the evaluation process can be found at http://www.texasobserver.org/showArticle.asp?ArticleFileName=020412_d1.htm



Exploring the Cognitive Level of Action Processing Via Reaching

Dr. Carl Gabbard

Professor

This is a continuing set of experiments designed to explore the programming characteristics involved in limb selection and reaching movements. Our quest, from a developmental perspective, is to identify the specific aspects of cognitive and neuromotor processes used in action processing. These experiments use an imagined (compared to) actual movement paradigm.  With this general design, we are able to examine the cognitive level of action processing.

 

Effects of the Home on Motor Development During the First 3 Years: A test of Affordances

This research project, being conducted by Dr. Carl Gabbard and Luis Rodrigues, has the intent to develop a unique observational research instrument to assess the quality and quantity of motor development affordances in the home for children birth to 3 years. The instrument has the potential for excellent research and applied value. Contemporary infant research suggests quite convincingly that an optimal level of development occurs only with a stimulating environment and strong contextual support. We anticipate that phase II will include children ages 3 to 6 years.

 


Ethnic Variation in Acceptance of Diabetes and Its Role in Successful Self-Management

Principle Investigator:  Dr. Ranjita Misra

This project focuses on the variations in acceptance of diabetes as a disease by adults of different ethnicities (Hispanics, African Americans, Asian Americans, and Caucasians) to manage Type 2 diabetes. Diabetes mellitus has reached epidemic proportions and is a significant public health problem. It is the sixth leading cause of death among adults, with the majority affected by Type 2 or Non-Insulin-Dependent Diabetes Mellitus (90-95% of diagnosed cases). Diabetes disproportionately affects minority populations, making it a major source of health disparity. The prevalence among minorities, i.e., African-Americans, Hispanics, and Asian Americans and Pacific Islander (API), is 2-6 times greater than that of the non-Hispanic white population (Hosey, Gordon, & Levine, 1998). While it is evident that diabetes self-management strategies will reduce their risk for severe complications and mortality, there is a paucity of research on ethnic variation in diabetes self-management. Further, patient acceptance of the disease, critical for compliance in self-management and lifestyle modifications, has rarely been researched. This grant is supported by Texas A&M University's College of Education and Human Development.

 


The Effects of Exercise, Menopause, and Estrogen Replacement Therapy on Visceral Adiposity in Women: The HERITAGE Family Study

 

Dr. John S. Green, Philip R. Stanforth, Dr. Jacques Gagnon, Dr. Arthur S. Leon, Dr. D. C. Rao, Dr. James S. Skinner, Dr. Claude Bouchard, Dr. Tuomo Rankinen, and Dr. Jack H. Wilmore

Visceral fat obesity (obesity in which fat accumulation is predominantly in the intraabdominal cavity) has been closely linked with disorders of both glucose and lipid metabolism, thereby significantly contributing to atherosclerotic heart disease risk. From clinical experiments, aging, physical inactivity, and sex hormone imbalance have been suggested as being influential in the accumulation of visceral fat. Contemporary studies investigating the possible role of menopause and estrogen replacement in this scenario have shown no consensus. Some suggest estrogen replacement reduces visceral fat deposition while others purport no effect. The purpose of this ongoing investigation is to examine data from the HERITAGE Family Study in an effort to determine if exercise, menopause, and estrogen replacement therapy influence visceral adiposity in women. The HERITAGE Family Study is a large multi-center clinical study exploring possible genetic influences on physiological response variability and the changes in risk factors for coronary disease and diabetes consequent to a regimen of endurance exercise.


Risk Factors For Diabetes Mellitus And Other Chronic Diseases Among Indian Americans In The United States - The AAPI-DIA Project

 

Investigators: Dr. Ranjita Misra & Dr. T.G.Patel


Indian Americans are represented under the broader classification of Asian Americans and Pacific Islanders (API). They represent the third largest Asian subcategory, and one of the fastest growing immigrant groups in the United States. However, they have been relatively neglected in terms of cardiovascular and diabetes research. Asian Indian immigrants worldwide experience excess mortality from coronary artery disease (CAD). Although mortality among Asian Indians from chronic diseases is comparable to other minority population, case fatality ratio from diabetes and CAD appears to be much higher. Studies that look at APIs in the aggregate mask the nature and extent of disparities among the subgroups (Japanese, Chinese, Korean, Indians, Vietnamese, etc).
The purpose of this pilot project is to (1) get baseline information on the prevalence of diabetes and other chronic disease, risk factors for chronic disease (especially diabetes and CAD), and health behaviors among Indian American males and females, and (2) explore other co-morbid conditions in this population. This grant is funded by Pfizer, and channeled through the American Association of Physicians of Indian Origin (AAPI).


The Quantification of Heart Disease Risk Perception and its Relationship to Actual Physiological Risk Markers in College Students. Investigators:

 

Dr. John S. Green, Wade Womack, Kari Meyer, Dr. Steve Crouse, Rose Schmitz, Kirsten Brekken, Dr. Sandy Kimbrough

Research in the area of heart disease risk perception is not abundant. A paucity of dated information suggests that adults often incorrectly perceive their risk, leaning toward an optimistic bias. The few recent publications that could be found indicate that heart disease risk perception may be related to an individual's perception of their overall general health and whether or not they perceive themselves susceptible to diseases other than heart disease. All of the studies noted above, however, used adults as subjects and no studies could be found describing heart disease risk perception in the young. Furthermore, to the authors' knowledge, no studies exist that examine the possibility of a relationship between an individual's perception of their risk and their actual risk as indicated by the number and relative severity of known physiological risk markers (serum lipids, blood pressure, body composition, etc.) The purpose of this ongoing study, therefore, is to quantify heart disease risk perception in college students and determine if a relationship exists between perceived and actual heart disease risk.


Community Needs Assessment: Opportunities for Student Participation in the Classroom

 

Investigators: Dr. Ranjita Misra & Dr. Danny Ballard

The intent of this pilot project is to incorporate community needs assessment research into the undergraduate classroom as an active learning project - one of the seven principles for good practice in undergraduate education. With a growing emphasis on undergraduate research and skills development, this project will take the students through the process that health educators use to identify gaps between current programs and required programs and place those needs (gaps in results) in a priority order. Needs assessments are useful to health educators primarily in planning programs and promoting effective public relations. It also helps to identify and diagnose health problems and in evaluating programs. Project will encompass mastery in a wide spectrum of skills: Identifying the sources of data (primary data - survey, nominal group process, community forums, focus groups, and observation; secondary data (government agencies, data available from health records, and current literature) and gathering data from target audience, analyzing the data collected, prioritizing the identified needs, as well as abstracting information concisely. Inclusion of the proposed project will help students identify need(s) to address community health problems and concerns. This grant is supported by Texas A&M University's Centers for Teaching Excellence Grant.


Diabetes Prevention Program: A Pilot Study In Rural India

 

Investigators: Dr. Ranjita Misra, Padmini Balagopal, & Dr. N. Kamalamma

Diabetes disproportionately affects Indians, making it a major source of health disparity. It is projected that 57.2 million individuals will have diabetes by 2025. The majority of individuals with diabetes are affected by Type 2, or Non-Insulin-Dependent Diabetes Mellitus (90-95% of diagnosed cases). Several factors such as population growth, genetic predisposition, high illiteracy rate, poverty, and sociological changes that impact lifestyle behaviors have been implicated in the etiology and increase of this disease in India. The objectives of this research is to determine whether diabetes education and prevention program is effective in reducing the incidence and complications, and improve self-management strategies through lifestyle changes in this rural population. The study design consists of a quasi-experimental approach with ten villages - 5 villages selected as the experimental site and 5 comparable villages as controls from the catchment's area of Gandhigram University. The sample will be comprised of a convenience group of 500 respondents in both the experimental and control villages (300 adults, 100 premenopausal women of childbearing age, and 100 children). Face-to-face interviews will be used as the data collection method. The intervention will comprise of a multi-pronged education of the individuals and families at various levels e.g., empowerment techniques, (e.g., self-help groups) and education programs (as part of the graduate/undergraduate student's internship and coursework on in the department of Nutrition & Dietetics through the University), to provide a continuity of this thrust on an ongoing basis.


The Effects of Resistance and Endurance Exercise on Lipid Metabolism and Lipoprotein Particle Size in Those with Low HDL.

 

Investigators: Dr. Stephen F. Crouse, Dr. Mark English, Dr. Judy Delp, & Dr. J. James Rohack

It is generally held that endurance training (ET) produces favorable changes in lipid metabolism, thereby lowering coronary heart disease (CHD) risk. While the mechanisms involved remain unclear, exercise-induced changes in lipid enzyme activity may be partly responsible. Of important clinical relevance, those with dyslipidemias, e.g., low HDL-C with elevated TG (lipid triad), have seldom been studied. Moreover, compared to the ET literature, there is a dearth of information regarding the effects of resistance training (RT) on lipoprotein-lipids. Reports are often contradictory, and information comparing the effectiveness of RT to ET at equivalent caloric expenditure is lacking. Published evidence shows that a significant portion of the lipid benefit often attributed to ET may actually result from short-term changes in lipid metabolism occurring acutely after one exercise session. More research is needed to differentiate the acute from the chronic effects of exercise training. At present, it is not clear that resistance exercise will produce substantial acute changes in lipids similar in magnitude to that of ET, and the influence of RT on the acute response to resistance exercise has not been studied. We are currently conducting a study in two groups of men and women volunteers; Group 1 with low HDL-C combined with elevated TG and Group 2 with both normal HDL-C and TG. Randomly selected subjects will undergo either RT or ET for 16 wks; a control group will not train. Before and after the training period we will characterize the acute effects of exercise on lipid metabolism by measuring the following variables before and after one session of resistance or endurance exercise. The variables to be measured are: TC, TG, HDL-C, HDL2&3-C, and LDL-C; apolipoproteins A-I and B; LDL and HDL particle size; and lipoprotein lipase (LPLa) and cholesterol ester transfer protein (CETPa) activity. We will test the following hypotheses in this study: 1) ET and RT will produce a less atherogenic lipid profile in those with low and normal HDL-C; 2) LPLa will be increased and CETPa will be decreased after 16 wks of RT and ET compared to the control group; 3) a single session of RT and ET exercise will produce increases in the activities of LPL and CETP that will result in lower TG and greater HDL-C levels. This study will provide information to be applied toward the optimization of primary and secondary prevention strategies to reduce CHD risk.


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