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The loss of skeletal muscle mass, strength, and physical function with age (sarcopenia) has numerous physiological and metabolic consequences that may lead to undesirable outcomes in older adults. Skeletal muscle plays a direct role in force production and its loss can lead to reduced mobility, loss of balance, increased incidence of falls and ultimately disability and loss of independence. In addition, muscle plays an underappreciated role in metabolism and sarcopenia has been associated with insulin resistance and metabolic syndrome. Consequently, identifying interventions that maintain muscle mass and function is a high priority therapeutic goal to improve quality of life and reduce medical costs associated with older adult populations. Dietary intake of the branch-chained amino acid leucine increases the rate of protein synthesis in skeletal muscle through mechanistic target of rapamycin complex 1 (mTORC1)-dependent as well as independent signaling pathways. However, physical inactivity reduces the ability to stimulate muscle protein synthesis in response to amino acids, termed anabolic resistance. Since older adults are at a greater risk of being inactive due to injury, illness or sedentary behavior, it is thought that anabolic resistance to amino acids may contribute to the development of sarcopenia.
One barrier to progress in this field is that while the ability of leucine to activate protein synthesis is well known, little is known about how activation of these pathways differentially controls the translation of specific mRNAs to support the anabolic effects of leucine, or how these changes in gene expression may vary in individuals with anabolic resistance. Therefore, the study proposes to define the leucine-induced translation program in skeletal muscle of older adults in response to inactivity-induced anabolic resistance using ribosome profiling and RNA-Seq. The study team will further analyze mRNA-specific ribosome coverage patterns, as well as monitor changes in expression of muscle- specific miRNAs, transcription factors, and RNA-binding proteins to develop hypotheses regarding the mechanisms involved in leucine-induced regulation of translation and mRNA abundance. The identification of the genes and pathways affected by leucine ingestion in older individuals with anabolic resistance as well as the mechanisms involved will provide critical information to rationalize new studies aimed at therapeutic interventions designed to prevent or offset the development of sarcopenia.
Ages Eligible for Study: 60 Years to 85 Years (Adult, Older Adult)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: Yes
- Age between 60-85 years
- Ability to sign informed consent
- Free-living, prior to admission
- Cardiac abnormalities considered exclusionary by the study physician (e.g., Chronic heart Failure, right-to-left shunt)
- Uncontrolled endocrine or metabolic disease (e.g., hypo/hyperthyroidism, diabetes)
- History of kidney disease or failure
- Vascular disease or risk factors of peripheral atherosclerosis. (e.g., uncontrolled hypertension, obesity, diabetes, hypercholesterolemia > 250 mg/dl, claudication or evidence of venous or arterial insufficiency upon palpitation of femoral, popliteal and pedal arteries)
- Risk of blood clotting including family history of thrombophilia, pulmonary emboli, myeloproliferative diseases including polycythemia (Hb>18 g/dL) or thrombocytosis (platelets>400x103/mL), and connective tissue diseases (positive lupus anticoagulant), hyperhomocystinemia, deficiencies of factor V Leiden, proteins S and C, and antithrombine III
- Use of anticoagulant therapy (e.g., Coumadin, heparin)
- Elevated systolic pressure >150 or a diastolic blood pressure > 100
- Cancer or history of successfully treated cancer (less than 1 year) other than basal cell carcinoma
- Implanted electronic devices (e.g., pacemakers, electronic infusion pumps, stimulators)
- Currently on a weight-loss diet or body mass index > 30 kg/m2
- Recent anabolic or corticosteroids use (within 3 months)
- History of stroke with motor disability
- A recent history (<12 months) of GI bleed
- History of liver disease
- History of respiratory disease (acute upper respiratory infection, history of chronic lung disease)
- Prior history of Heparin-Induced Thrombocytopenia
- An HbA1c value at or greater than 6.5%
- Subjects may not participate if they have utilized ionizing radiation (either radioisotopes or diagnostic x-rays) during the past 12 months.
- Any other condition or event considered exclusionary by the PI and faculty physician
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
University of Utah, Salt Lake City, Utah, United States, 84112