Pilot Project 1: P.I. Elena Volpi, M.D., Ph.D. "A novel method to measure myofibrillar protein turnover."

Dr. Elena Volpi, M.D., Ph.D., Assistant Professor in the Division of Geriatric Medicine, (Dr. Robert Wolfe, mentor) Dr. Volpi conducted a study to develop stable isotope methods to measure degradation of specific muscle proteins and to assess the relative contribution of the three major proteolytic pathways (ubiquitin-proteasome, lysosomal, and calcium-dependent) in degrading myofibrillar versus total muscle proteins.

Pilot Project 2: P.I. Charles A. Stuart, M.D. "Aging and the expression of muscle glucose transporters."

Charles Stuart, M.D., Professor of Medicine and director of the Clinical Research Center examined the expression and distribution of glucose transporters in muscle biopsies of young and old subjects. He hypothesizes that changes in the distribution of these transporters and the resultant decline in glucose uptake contribute to decrease in muscle function with age.

Pilot Project 3: Taylor J. Marcell, Ph.D. "The effects of testosterone administration on skeletal muscle gene expression from healthy older men using the DNA array."

Taylor J. Marcell, Ph.D., ATC examined the effect of hormone (testosterone) on human skeletal muscle gene expression using cDNA microarray analysis of age-related sarcopenia muscle. These analyses provided basic information on the families of genes whose expressions are affected by sarcopenia and whether their expression is affected by the hormone-mediated amelioration of this loss of muscle mass. The preparation of mRNAs from control and hormone-treated young vs. aged males is in progress. The Pepper Center Molecular Biology Core Facility has established a microarray capability and will participate in conducting and analyzing these experiments.

Pilot Project 4: John Pappaconstantinou, Ph.D. William H. Boyleston, Graduate Student, "Role of Myostatin in Regulation of Sarcopenia."

John Papaconstantinou, Ph.D., and William Hal Boyleston examined the role of myostatin, a member of the TGF-b superfamily and regulator of skeletal muscle homeostasis, in the age-associated loss of muscle mass, and will be able to assess the effects of nutritional, hormonal and exercise interventions on myostatin expression.

Presentations

Dihydropyridine Receptor Expression in Aging Skelletal Muscle.
Philip Palade, Ph.D.

Eeffects of Short-Term Oxandrolone Administration on Protein Metabilism in Elderly Men and Women. Melinda Moore, Ph.D.

Dynamic Balance in Older Adults Ronita Cromwell, Ph.D.

Age-associated Alteration in Cardiovascular Inflammatory Cascades. Hiroshi Saito, Ph.D.

Sarcopenia in Aging and After Injury. Taylor Marcell, Ph.D.

Expression of Glucose Transporters in the Muscle of Older Americans. Charles Stuart, Gary Wen, Taylor Marcel, Thomas Wood.

Human Muscle Basal Glucose Transporter Gene Expression. Charles Stuart, John Copland, Gary Wen, Thomas Wood.

Short-term Oxandrolone Administration Has a Different Effect on Muscle Protein Regulation in Older Men and Women. M Sheffield-Moore, E Volpi, SE Wolf, C Gilkison, J Jiang, D Paddon-Jones, DL Chinkes, RR Wolfe, AA Ferrando, and RJ Urban

Acute Aerobic Exercise Stimulates Muscle Protein Synthesis in Older Men. M Sheffield-Moore, CW Yeckel, E Volpi, SE Wolf, B Morio, D Paddon-Jones, DL Chinkes, HA Singh and RR Wolfe

Publications

Volpi E, B Mittendorfer, RR Wolfe. Exogenous glucose limits the anabolic effect of amino acids on muscle protein in the elderly. Submitted.

Wolfe, RR and E. Volpi. Insulin and protein metabolism. Handbook of Physiology, In Press.

Wolfe RR, A Ferrando, M Sheffield-Moore, R Urban. Testosterone and muscle protein metabolism. Mayo Clin Proc 75:S55-S60, Jan 2000.

Mittendorfer B. Volpi E. Wolfe RR. Whole body and skeletal muscle glutamine metabolism in healthy subjects. American Journal of Physiology - Endocrinology & Metabolism. 280(2):E323-33, 2001 Feb.

Volpi E. Mittendorfer B. Rasmussen BB. Wolfe RR. The response of muscle protein anabolism to combined hyperaminoacidemia and glucose-induced hyperinsulinemia is impaired in the elderly. Journal of Clinical Endocrinology & Metabolism. 85(12):4481-90, 2000 Dec.

Volpi E. Rasmussen BB. Nutrition and muscle protein metabolism in the elderly. Diabetes, Nutrition & Metabolism - Clinical & Experimental. 13(2):99-107, 2000 Apr.

Volpi E. Jeschke MG. Herndon DN. Wolfe RR. Measurement of skin protein breakdown in a rat model. American Journal of Physiology - Endocrinology & Metabolism. 279(4):E900-6, 2000 Oct.

Volpi E. Mittendorfer B. Wolf SE. Wolfe RR. Oral amino acids stimulate muscle protein anabolism in the elderly despite higher first-pass splanchnic extraction. American Journal of Physiology. 277(3 Pt 1):E513-20, 1999 Sep.

Volpi E. Sheffield-Moore M. Rasmussen BB. Wolfe RR. Basal muscle amino acid kinetics and protein synthesis in healthy young and older men. JAMA. 286(10):1206-12, 2001 Sep 12.

Wolfe R. Ferrando A. Sheffield-Moore M. Urban R. Testosterone and muscle protein metabolism. Mayo Clinic Proceedings. 75 Suppl:S55-9; discussion S59-60, 2000 Jan.

Sheffield-Moore M. Androgens and the control of skeletal muscle protein synthesis. Annals of Medicine. 32(3):181-6, 2000 Apr.

Sheffield-Moore M. Wolfe RR. Gore DC. Wolf SE. Ferrer DM. Ferrando AA. Combined effects of hyperaminoacidemia and oxandrolone on skeletal muscle protein synthesis. American Journal of Physiology - Endocrinology & Metabolism. 278(2):E273-9, 2000 Feb.

Ferrando AA. Stuart CA. Sheffield-Moore M. Wolfe RR. Inactivity amplifies the catabolic response of skeletal muscle to cortisol. Journal of Clinical Endocrinology & Metabolism. 84(10):3515-21, 1999 Oct.

Pilot Project 1: Jeffery D. Ceci, Ph.D., Assistant Professor, Sealy Center for Cancer Cell Biology. Project title, "Analysis of Tpl2 Knockout Mice for Oxidative Stress and Aging". This study is based on using a potential mouse model to study oxidative stress using tumor progression locus-2 (Tpl2) knockout mice. Specific aims of this pilot project include: 1) to determine whether homozygous Tpl2 knockout mice live longer than control mice; 2) to determine whether homozygous Tpl2 knockout mice injected with D-galatosamine/LPS are more resistant to oxidative stress compared to their wild type littermates; 3 to determine whether Tpl2 knockout mice have reduced expression of insulin like growth factor.

Pilot Project 2: Philip Palade, Ph.D., Professor, Physiology and Biophysics. Project title, "Causes of Decreased Dihydropyridine Binding in Aging Rodent Muscle". This pilot project will examine the possible role of dihydropyridine receptor in aging muscle as a possible candidate for eventual therapeutic intervention aimed at ameliorating muscle strength in the elderly.

Pilot Project 3: John Papaconstantinou, Ph.D. Professor, Human Biological Chem & Genetics (HBC&G). Project title, "Genomics-Proteomics Genetics of Aging Program". This pilot project focuses on extending the capabilities at UTMB for the development of custom genomic and proteomic microarrays.

Presentations

Effects of Amino Acid Supplementation on Protein Metabolism in Young and Elderly Individuals.
D. Paddon-Jones, M. Sheffield-Moore, X. J. Zhang, S. E. Wolf, A. P. Sanford, A. A. Ferrando and R. R. Wolfe

Oral Intake of Whey Protein or Essential Amino Acids Improves Muscle Protein Net Synthesis in the Elderly.
X. J. Zhang, Department of Surgery SBI, D. Paddon-Jones, S. E. Wolfe, E. Volpi, and R. R. Wolfe

Short-term Oxandrolone Administration Has a Different Effect on Muscle Protein Regulation in Older Men and Women.
M. Sheffield-Moore, E. Volpi, S. E. Wolf, C. Gilkison, J. Jiang, D. Paddon-Jones*, D. L. Chinkes*, R. R. Wolfe*, A. A. Ferrando, and R. J. Urban.

Acute Aerobic Exercise Stimulates Muscle Protein Synthesis in Older Men.
M. Sheffield-Moore, C. W. Yeckel, E. Volpi, S. E. Wolf, B. Morio, D. Paddon-Jones, D. L. Chinkes, H. A. Singh and R. R. Wolfe.

Acute Resistance Exercise Stimulates Muscle Protein Synthesis in Older Men.
M. Sheffield-Moore, D. Paddon-Jones, S. E. Wolf, D. L. Chinkes, E. R. Casiano and R. R. Wolfe.

Storage of Plasma Fatty Acids in Skeletal Muscle Triglyceride is Elevated in Healthy Older Men Before and After Acute Aerobic Exercise.
C.W. Yeckel, M. Sheffield-Moore, B. Morio, S.E.Wolf, E.Volpi, D.L. Chinkes, H.A. Singh, and R.R.Wolfe.

Causes of Decreased Dihydropyridine Binding in Aging Rodent Muscle
C. Dettbarn and P. Palade.

Insulin/IGF-1 Signaling in the Snell Dward Brain.
W. H. Boylston III, C. C. Hsieh, and J. Papaconstantinou, UTMB Department of Human Biological Chemistry and Genetics

Insulin Signaing is Attenuated in the Long-lived Sell Dwarf Mice.
C. C. Hsieh, K. Flurkey, D. E. Harrison, J. Papaconstantinou,

Localization of BRCA2 in Young and Aged Mouse Liver.
M. A. Madsen, J. H. DeFord, and J. Papaconstantinou.

Publications

Al Snih S, Markides K, Ray L, Goodwin JS. Hand grip strength and mortality in Mexican-Americans. Journal of American Geriatrics Society, 50: 1250-1256, 2002.

Angel RJ, Angel JL, Markides KS. Stability and change in health insurance among older Mexican Americans: Longitudinal evidence from the Hispanic - EPESE. American Journal of Public Health, 92(8): 1264-1271, 2002.

Brill KT, Weltman AL, Gentili A, Patrie JT, Fryburg DA, Hanks JB, Urban RJ, Veldhuis JD. Single and combined effects of growth hormone and testosterone administration on measures of body composition, physical performance, mood, sexual function, bone turnover, and muscle gene expression in healthy older men. JCEM 87:5649-5657, 2002.

Chiriboga, D.A., Black, S.A., Aranda, M., Markides, K.S. Stress and Depressive Symptoms among Mexican American Elders. Journal of Gerontology: Psychological Sciences, 57B(6): P559-P568, 2002.

Ferrando AA, Sheffield-Moore M, Yeckel CW, Gilkison C, Jiang J, Marcell T, Achacosa A, Lieberman SA, Tipton KD, Wolfe RR, Urban RJ. Testosterone administration to older men improves muscle function: molecular and physiological mechanisms. American Journal of Physiology Endocrinology and Metabolism 282, E601-E607, 2002.

Ferrando AA, Paddon-Jones D, Wolfe RR. Alterations in protein metabolism during space flight and inactivity. Nutrition. 18(10):837-41, 2002.

Flurkey K, Papaconstantinou J, and Harrison DE. The Snell Dwarf Mutation Pit 1dw Can Increase Life Span in Mice. Mech Age. Dev. 123(2-3):121-30, 2002.

Gardner AW. Killewich LA. Association between physical activity and endogenous fibrinolysis in peripheral arterial disease: a cross-sectional study. Angiology 53(4):367-74, 2002.

Gore DC, Chinkes DL, Hart DW, Wolf SE, Herndon DN, Sanford AP. Hyperglycemia exacerbates muscle protein catabolism in burn-injured patients. Critical Care Medicine 30(11):2438-42, 2002.

Hsieh C-C, DeFord, JH, Flurkey K, Harrison DE, and Papaconstantinou J. Effects of the Pit1q Mutation on the Insulin Signaling Pathway: Implications on the Longevity of the Long-lived Snell dwarf mouse. Mech Age Dev 123:1245-1255, 2002.

Hsieh C-C, DeFord JH, Flurkey K, Harrison DE and Papaconstantinou J. Implications of the Insulin Signaling Pathway in Snell dwarf Mouse Longevity: A Similarity with C. elegans Longevity Paradigm, Mech Age Dev 123:1229-1244, 2002.

Nguyen HT, Black SA, Ray LA, Espino DV, Markides KS. Predictors of decline in MMSE scores among older Mexican Americans. Journal of Gerontology: Medical Sciences 57 (3):M181-M185, 2002.

Ostir GV, Goodwin JS, Markides KS, Ottenbacher KJ, Balfour J, Guralnik JM. Differential effects of pre-morbid physical and emotional health on recovery from acute illness. Journal of the American Geriatric Society 50(4):713-8, 2002.

Ottenbacher KJ, Ostir GV, Peek MK, Goodwin JS, and Markides KS. Diabetes Mellitus as a risk factor for hip fracture in Mexican American older adults. Journals of Gerontology: Medical Sciences. J Gerontol: Med Sci, 57A(10), M648-M653. 2002

Ottenbacher, Kenneth J., Laurence J. Branch, Laura Ray, Vera S. Gonzales, M. Kristen Peek, and Martha R. Hinman. The reliability of upper and lower extremity strength testing in a community survey of older adults. Arch Physical Medicine and Rehabilitation, 83, 1423-1427, 2002.

Rasmussen BB. Holmback UC. Volpi E. Morio-Liondore B. Paddon-Jones D. Wolfe RR. Malonyl coenzyme A and the regulation of functional carnitine palmitoyltransferase-1 activity and fat oxidation in human skeletal muscle. J of Clinical Investigation. 110(11):1687-93, 2002.

Zhang XJ. Chinkes DL. Wolfe RR. Measurement of muscle protein fractional synthesis and breakdown rates from a pulse tracer injection. American Journal of Physiology - Endocrinology & Metabolism. 283(4):E753-64, 2002.

1. Arny A. Ferrando, PhD., Project title, "Muscle Function in Older Individuals: The Relationship between Oxidative Capacity and Muscle Function"
   This is a pilot project that will lead to the investigation of nutritional and exercise interventions to improve muscle function in older individuals. The following specific aims have been proposed:
   • To develop the methodology and hardware requirements for studying energy substrates by phosphorus magnetic resonance spectroscopy (MRS) in the calf muscle of older individuals before, during, and after exercise.
   • To further determine the relationship between muscle energy metabolism and muscle function in this population.
   The development of this valuable analytic tool will allow future testing of our hypothesis relating a diminished capacity for energy metabolism to a decrease in mitochondrial protein turnover. We must first adapt the MRS equipment in the F. Marie Hall Magnetic Resonance Laboratory to accommodate an exercise protocol of the calf. This entails the development of exercise hardware, computer interface, exercise load quantification, and interpretation software.
2. Owen P. Hamill, Ph.D., Project title, "Mechanical stimulation (exercise) of animal cells increases constitutive membrane trafficking and ATP release that may delay the deleterious effects of aging"
   The main aim of this pilot project was to test our hypothesis that mechanical stimulation promotes ATP release by increasing the membrane trafficking of protein transport vesicles enriched in ATP. Our previous studies were based on pharmacological interventions involving agents that reversibly disrupt membrane trafficking and protein secretion and thereby block ATP release. We also demonstrated using integrin binding peptides that the mechanosensitive (MS) signaling pathway was integrin-dependent (Maroto & Hamill, 2001). Since our work was published there has been increased interest in the concept of MS membrane trafficking.
3. Lisa J. Gould, M.D., Ph.D., Project title, "Wound Healing and Aging"
   Aging impairs many aspects of wound healing. Human and animal studies have shown that migration of inflammatory cells to the wound bed is delayed and there is a general decline in cellular function. The age-related decline in wound healing is magnified when combined with ischemia. This has been demonstrated by the lack of angiogenesis in an aged mouse hindlimb model of ischemia and significantly reduced breaking strength, granulation tissue deposition and epithelial ingrowth in an aged rabbit ear model of ischemia.
   
   The hypothesis for this pilot project is that two physical modalities thought to increase angiogenesis can be used to improve wound healing in the aged. Because of the lack of an accessible animal model, the majority of molecular data regarding the combination of age and ischemia comes from cell culture. Although this approach has contributed important evidence that the response to hypoxia in aged cells is diminished, these studies have focused on down-stream mediators, such as metalloproteinases and inflammatory cytokines, rather than the mechanisms that elicit this response. To address these problems, we have developed an animal model of tissue ischemia that will allow us to delineate the complex cellular interactions not mimicked by cell culture. This model has been designed to correlate macroscopic wound healing parameters with histological and biochemical changes leading to neovascularization and wound healing.

Publications

Al Snih S, Markides KS, Ostir GV, Ray LA, Goodwin JS. Predictors of recovery in activities of daily living among older Mexican Americans. Aging: Clinical and Experimental Research (in press).

Copland JA, Davies PJ, Shipley GL, Wood CG, Urban RJ. The use of DNA microarrays to assess clinical samples. The transition from bedside to bench to bedside. Recent Progress in Hormone Research 58: 25-53, 2003.

Ferrando AA, Sheffield-Moore M, Paddon-Jones D, Wolfe RR, Urban RJ. Differential anabolic effects of testosterone and amino acid feeding in older men. Journal of Clinical Endocrinology and Metabolism 88, 358-362, 2003.

Ferrando AA, Sheffield-Moore M, Paddon-Jones D, Wolfe RR, Urban RJ. Differential anabolic effects of testosterone and amino acid feeding in older men. J of Clin Endocrinol & Metabolism. 88(1):358-62, 2003.

Hsieh C-C, and Papaconstantinou J. The Effect of Aging on p38 Signaling Pathway Activity in the Mouse Liver and in Response to ROS Generated by 3-Nitropropionic Acid, Mech Age Dev 123:1423-1435, 2003.

Hsieh C-C, and Papaconstantinou J. Age-Associated Changes in SAPK/JNK Signaling in Response to the Generation of ROS by 3-Nitropropionic Acid, Mech Age Dev (In Press).

Peek, M. Kristen, Kenneth J. Ottenbacher, Kyriakos S. Markides, and Glenn V. Ostir. Examining the disablement process among older Mexican American adults. Social Science and Medicine (In Press).

Peek, M. Kristen and Kyriakos S. Markides. Blood pressure concordance among older Mexican American married couples. Journal of the American Geriatrics Society (In Press).

Tipton, K.D., E. Børsheim, S.E. Wolf, A.P. Sanford, and R.R. Wolfe. Acute response of net muscle protein balance reflects 24h balance following exercise and amino acid ingestion. Am. J. Physiol. (Endocrinol. Metab.). 284:E76-89, 2003.

Presentations

Protemic Analysis of Vastus Lateralis Muscle in Hemiparetic Stroke Patients: A Progress Report.
J.P. Rabek, M. Marchette, W.H. Boylston III, J. Papaconstantinou*, R.F. Macko and C. Hafer-Macko. Department of Human Biological Chemistry & Genetics, The University of Texas Medical Branch, Galveston, Texas and Baltimore VA and University of Maryland School of Medicine, University of Maryland, Baltimore, MD.

A Dose Response Study Examining the Protein Metabolic Effects of Essential amino Acid Supplementation in the Elderly.
M. Sheffield-Moore, D. Paddon-Jones, C. Gilkison*, S.E. Wolf, D.W. Lackan, R.R. Wolfe and R.J. Urban. Departments of Surgery and Internal Medicine, The University of Texas Medical Branch, Galveston, Texas, 77555.

Leg Muscle Metabolism in Elderly Subjects With Peripheral Arterial Disease.
L Killewich*, M Moore, M Murakami, J Goodwin, R Wolfe. Departments of Surgery and Medicine and Sealy Center for Aging, The University of Texas Medical Branch, Galveston, TX.