During aging, humans can lose up to one third of their skeletal muscle mass. Such aging-associated muscle loss is referred to as sarcopenia. Sarcopenia is a contributing factor to a number of serious public health issues, including bone fractures, loss of ambulation and overall frailty in the elderly. While some advances have been made in understanding sarcopenia using animal models, rodent models most commonly used to study this aspect of muscle biology require aging animals 2-3 years, an age that is at or beyond the animal's normal lifespan. Here we describe a new mouse model for sarcopenia where most relevant hallmarks, including loss of muscle mass, size and strength are evident by 6 months of age. These phenotypes result from myofiber-specific deletion of Pofut1 (Skeletal alpha actin (Sk)-CreTgPofut1loxP), or Protein O-fucosyltransferase 1. Pofut1 is an essential glycosyltransferase that is required for ligands to bind to Notch receptors. Notch receptors and Notch ligands have been shown to be important mediators of the biology underlying the reduced mitotic activity of satellite cells, the principal regenerative pool of muscle stem cells, with age This proposal will provide the first demonstration that Notch activity in the skeletal myofiber als contributes to muscle aging and will allow the specific study of the role of myofiber Notch receptors in muscle regeneration, muscle growth and muscle disease.

Public Health Relevance

Sarcopenia, the normal loss of muscle mass and strength during aging, is a significant health issue for the elderly. This proposal will study an important molecular process that underlies the development of sarcopenia, focusing on the contribution of Notch receptors and muscle regeneration, and describe a new animal model to study this phenomenon.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AR060412-02
Application #
8454456
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Boyce, Amanda T
Project Start
2012-04-05
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$154,755
Indirect Cost
$47,880
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205