Motor dysfunction and skeletal muscle wasting are major causes of poor quality of life, increased health care costs, and institutionalization in the elderly. However, age-related dysfunction of the respiratory muscles has an even greater impact on quality of life: impairment of the aging diaphragm disrupts a number of important behaviors, such as breathing, airway protective reflexes (coughing and sneezing), and voice. Since the diaphragm and accessory respiratory muscles must be active throughout life to sustain ventilation, it is not surprising that their response to aging diverges from that seen in other skeletal muscles. In contrast to limb muscles, atrophy does not explain the weakness and increased fatigability of the aging diaphragm;however, since the diaphragm is constantly active it may have a need for constant remodeling. Indirect evidence for this notion stems from the fact that there is an apparent depletion of satellite cells in diaphragm muscle of mdx mice, rendering it more susceptible to damage. Whether a similar situation exists for aging diaphragm muscle and whether satellite cell depletion and/or dysfunction play a role in decreased diaphragm function with age are completely unexplored issues. We are in the unique position to test the role of satellite cells in diaphragm muscle with aging using the Pax7-DTA mouse, which allows for temporal and specific control of satellite cell ablation;we showed previously that >90% of satellite cells are ablated in response to tamoxifen treatment using this genetic model. It is currently unknown what the role of satellite cells is in the maintenance of diaphragm function with aging by itself, or when the muscle is functionally challenged. Therefore our hypothesis is that satellite cells are necessary to sustain the structure and function of the aging diaphragm, allowing it to withstand functional challenges. We will test the hypothesis using two specific aims.
In Aim 1 we will determine whether satellite cell ablation in Pax7-DTA mice alters structure and function of the diaphragm with aging. Satellite cells will be ablated at 4 months of age and mice will be tested at 6, 18, and 24 months of age. The efficiency of satellite cell ablation will be measured, and analyses will be performed to assess morphological as well as functional changes in the diaphragm, and in ventilation in vivo.
In Aim 2 we will establish whether satellite cell ablation impairs the ability of the aging diaphragm to adapt to functional challenges. Satellite cells will be ablated at 4 months of age and mice will be subjected to normobaric hypoxia for 4 weeks or running activity for 8 weeks. Analyses will be performed as in Aim 1 and compared to measures obtained from mice in Aim 1. We expect that satellite cell ablation causes detrimental functional and structural changes in the aged diaphragm, and that the ability of the diaphragm to adapt to changes in functional demand is impaired, particularly in the aged. With the studies proposed in this application, we will provide insight into the role of satellite cells in diaphragm muscle with advancing age, which is an unexplored area;this knowledge will enable us to develop effective intervention strategies for the loss of diaphragm function with age.

Public Health Relevance

Diaphragm muscle function is decreased with age, but the role of muscle stem cells (satellite cells) in this process is unclear. We propose to study whether satellite cells are required to maintain muscle structure and function of diaphragm with age and in response to a functional challenge. The knowledge from these studies will enable us to design therapies to combat decreased ventilatory reserve with age.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Skeletal Muscle Biology and Exercise Physiology Study Section (SMEP)
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Williams, John
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University of Kentucky
Physical Medicine & Rehab
Sch Allied Health Professions
United States
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Murach, Kevin A; Confides, Amy L; Ho, Angel et al. (2017) Depletion of Pax7+ satellite cells does not affect diaphragm adaptations to running in young or aged mice. J Physiol 595:6299-6311
Fry, Christopher S; Lee, Jonah D; Mula, Jyothi et al. (2015) Inducible depletion of satellite cells in adult, sedentary mice impairs muscle regenerative capacity without affecting sarcopenia. Nat Med 21:76-80