The PI's short-term goal is to obtain the training required to complete the proposed studies. His long-term goal is to become an independent researcher and to develop his own research program investigating the mechanism of weight loss and skeletal muscle atrophy in healthy and diseased elderly. During this award, the PI will gain experience in several laboratory and clinical research techniques associated with the measurement of skeletal muscle protein metabolism in humans using stable isotopes, arterio-venous balance and skeletal muscle biopsy methodologies. The mentoring team and the facilities available within the College Of Medicine are an ideal environment for the training of junior scientists. Patients with chronic heart failure frequently experience skeletal muscle atrophy which limits functional Capacity by reducing muscular strength and endurance. Moreover, muscle atrophy is associated with increased morbidity and mortality. The primary goal of the proposed studies is to determine the pathophysiological mechanisms underlying the loss of skeletal muscle mass in patients with chronic heart failure. The primary hypothesis is that increased skeletal muscle protein Catabolism in the postabsorptive state and reduced skeletal muscle protein anabolism in the postprandial state promotes skeletal muscle atrophy in heart failure patients. We will measure skeletal muscle protein balance (i.e., difference between synthesis and breakdown) using a combination of arteriovenous balance and stable isotope tracer techniques under postabsorptive (24 hour fast) and simulated-postprandial conditions (euglycemic hyperinsulinemia with concomitant hyperaminoacidemia) in cachectic and noncachectic heart failure patients and healthy controls. We will assess skeletal muscle protein balance during these experimental manipulations to probe for defects in postabsorptive and postprandial muscle protein balance that may contribute to skeletal muscle atrophy. In this design, noncachectic heart failure patients will serve as a diseased control group and healthy controls as a non-diseased control group. The secondary goal is to measure and compare the synthesis rate of skeletal muscle myosin heavy chain between heart failure patients and healthy controls and examine its relationship to reduced muscular strength in heart failure patients. Our secondary hypothesis is that reduced synthesis of myosin heavy chain in heart failure patients will be related to reduced muscular strength. The fractional synthetic rate of myosin heavy chain will be assessed by measuring the incorporation of [1,2- 13C2]leucine into skeletal muscle protein. These experiments will provide new information regarding the pathophysiological mechanisms responsible for the loss of skeletal muscle mass and strength in heart failure patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AR002125-05
Application #
6660328
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Nuckolls, Glen H
Project Start
1999-08-01
Project End
2005-01-31
Budget Start
2003-08-01
Budget End
2005-01-31
Support Year
5
Fiscal Year
2003
Total Cost
$114,895
Indirect Cost
Name
University of Vermont & St Agric College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
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Callahan, Damien M; Toth, Michael J (2013) Skeletal muscle protein metabolism in human heart failure. Curr Opin Clin Nutr Metab Care 16:66-71
Toth, Michael J; LeWinter, Martin M; Ades, Philip A et al. (2010) Impaired muscle protein anabolic response to insulin and amino acids in heart failure patients: relationship with markers of immune activation. Clin Sci (Lond) 119:467-76
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Toth, M J; MacCoss, M J; Poehlman, E T et al. (2001) Recovery of (13)CO(2) from infused [1-(13)C]leucine and [1,2-(13)C(2)]leucine in healthy humans. Am J Physiol Endocrinol Metab 281:E233-41