Skeletal muscle disuse is an important contributing factor to physical disability. Disuse is more frequent in the elderly and they are more susceptible to its debilitating effects because of their diminished physiological reserve. Despite these facts, the mechanisms whereby disuse promotes skeletal muscle contractile dysfunction in this population remain largely undetermined. Therefore, we propose to systematically test for modifications of single muscle fiber structure and function that underlie contractile dysfunction. Elderly individuals characterized by chronic muscle disuse will be compared to carefully-matched controls with normal activity levels. Thereafter, elderly with chronic disuse will undergo an exercise intervention to remediate muscle disuse. We hypothesize that muscle disuse impairs contractile function, in part, through alterations in myosin kinetics, myofilament protein content and the mechanical properties of the myofilament lattice and that exercise rehabilitation will counteract these deficits.
Aim 1 will examine the effect of disuse on mechanical, kinetic and structural properties and molecular composition of single muscle fibers in cases and controls.
Aim 2 will investigate how increasing muscle use in elderly with chronic disuse via exercise training affects muscle fiber mechanical, kinetic and structural properties and molecular composition. Innovations in our laboratories have enabled assessment of muscle function at the level of the myosin-actin cross-bridge in humans for the first time. In combination with other mechanical, biochemical and anatomical measurements, these translational studies will provide the first comprehensive evaluation of the cellular and molecular mechanisms through which muscle disuse alters skeletal muscle structure and contractile function in elderly humans. This knowledge can assist in the development and refinement of preventative and corrective therapies for disability by tailoring these approaches to address specific molecular defects.

Public Health Relevance

Skeletal muscle disuse is an important contributing factor to disability in the elderly. Despite the fact that elderly are more likely to experience disuse and lack the physiological reserve to buffer its detrimental effects, the cellular and molecular mechanisms that underlie disuse-related muscle contractile dysfunction remain largely unstudied. Knowledge gained from the proposed studies will assist in the development and refinement of preventative and corrective clinical therapies for disability by tailoring these approaches to address specific cellular and molecular defects.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AG033547-05
Application #
8688122
Study Section
Skeletal Muscle Biology and Exercise Physiology Study Section (SMEP)
Program Officer
Joseph, Lyndon
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Vermont & St Agric College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Burlington
State
VT
Country
United States
Zip Code
05405
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Callahan, Damien M; Miller, Mark S; Sweeny, Andrew P et al. (2014) Muscle disuse alters skeletal muscle contractile function at the molecular and cellular levels in older adult humans in a sex-specific manner. J Physiol 592:4555-73
Tanner, Bertrand C W; McNabb, Mark; Palmer, Bradley M et al. (2014) Random myosin loss along thick-filaments increases myosin attachment time and the proportion of bound myosin heads to mitigate force decline in skeletal muscle. Arch Biochem Biophys 552-553:117-27
Miller, Mark S; Bedrin, Nicholas G; Callahan, Damien M et al. (2013) Age-related slowing of myosin actin cross-bridge kinetics is sex specific and predicts decrements in whole skeletal muscle performance in humans. J Appl Physiol (1985) 115:1004-14