Aging is accompanied by a gradual loss of skeletal muscle size and function known as sarcopenia. A contributor to falls, frailty and loss in functional mobility in the elderly, disability associated with sarcopenia is considered to be a burgeoning cost to the US healthcare system. The reasons for age-related skeletal muscle decline and hence therapeutic strategies remain elusive. Features of sarcopenic skeletal muscle include ongoing cycles of denervation and reinnervation, loss of functional neuromuscular junctions (NMJs) and depletion of resident stem cells (satellite cells). However, any interrelationship between age-related satellite cell and NMJ decline remains ambiguous. Hence, this proposal is designed to elucidate the fates and roles of satellite cells and derived progenitors at degenerating NMJs with age. In addition, we propose a strategy to attenuate age-related NMJ decline by specific manipulation of satellite cells. To accomplish these objectives satellite cell-specific mouse genetic models and confocal immunofluorescence imaging of NMJs will be used. We have generated preliminary data that show loss of post-synaptic myonuclei at NMJs together with myofiber type transitions consistent with neuromuscular disruption in aged skeletal muscle. In parallel studies, we find satellite cells are required for the maintenance of post-synaptic myonuclei, myofiber type properties and the reinnervation of adult NMJs by motor nerve terminals in response to experimental neuromuscular disruption. Finally, we demonstrate that satellite cell specific forced expression of the receptor tyrosine kinase feedback regulator sprouty1 (Spry1) is sufficient to attenuate decline of post-synaptic myonuclei at aging NMJs. We will solidify our preliminary findings through the assessment of NMJ integrity, satellite cell proximity, post-synaptic myonuclei and myofiber type properties in skeletal muscles of various ages. We will also assess the consequences of satellite cell depletion and satellite cell specific Spry1 forced expression on the maintenance of NMJs and myofiber type properties with age.
The specific aims of this proposal are: 1) To identify whether loss of post-synaptic myonuclei is a feature of aged degenerated NMJs, define regulators of age-related myofiber phenotypic transitions connected to NMJ decline and examine satellite cell derived contributions at aging NMJs, 2) To examine if satellite cell depletion accelerates age-related declines in NMJ integrity and NMJ regulated myofiber properties and 3) To determine if satellite cell-specific forced Spry1 expression attenuates loss of; post-synaptic myonuclei, NMJ integrity and maintains NMJ regulated myofiber properties with age.

Public Health Relevance

We have identified loss of skeletal muscle stem cells (satellite cells) and myonuclei in the vicinity of aged NMJs together with myofiber type transitions consistent with neuromuscular disruption in aged skeletal muscle. We have also found roles for satellite cells in the maintenance of NMJ myonuclei and NMJ reinnervation in response to experimental neuromuscular disruption. Finally, we observe satellite cell specific forced expression of the receptor tyrosine kinase (RTK) and mitogen activated protein kinase (MAPK) negative feedback regulator sprouty1 (Spry1) can attenuate the loss of satellite cells and myonuclei in the vicinity of aging NMJs. Our proposal will: 1) Identify whether loss of satellite cell derived post-synaptic myonuclei at NMJs are features of aging, 2) Define regulators of age-related myofiber transitions connected to NMJ disruption, 3) Examine the consequences of satellite cell depletion on the decline of NMJ and NMJ-regulated myofiber properties with age and 4) Assess the ability of satellite cell specific forced expression of Spry1 to attenuate age-related deficits in NMJ integrity and myofiber properties. Data generated by this proposal will likely implicate satellite cells and Spry1 signaling in the regulation of NMJ maintenance with age. In addition, the data generated should identify potential therapeutic targets to attenuate NMJ loss with age and the progression of sarcopenia.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG051456-01
Application #
9000483
Study Section
Special Emphasis Panel (ZAG1)
Program Officer
Williams, John
Project Start
2015-09-30
Project End
2020-05-31
Budget Start
2015-09-30
Budget End
2016-05-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Rochester
Department
Orthopedics
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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Liu, Wenxuan; Wei-LaPierre, Lan; Klose, Alanna et al. (2015) Inducible depletion of adult skeletal muscle stem cells impairs the regeneration of neuromuscular junctions. Elife 4:
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