Metabolic response to contraction in a 3D engineered muscle tissue model of aging

Title: Metabolic response to contraction in a 3D engineered muscle tissue model of aging
Decreased skeletal muscle mass, specific force, increased overall fatty infiltration in the skeletal muscle, frailty
and depressed energy maintenance are all associated with increased oxidative stress decline in mitochondrial
function and the development of sarcopenia with age. Mitochondrial response to exercise has been shown to be
partially mediated through signaling control following muscle contraction. We have previously developed
protocols to test mitochondrial function following high-intensity interval (HII) and low-intensity steady state (LISS)
muscle contraction in vivo. Following HII, young skeletal muscle mitochondria increased fatty acid oxidation
compared to non-stimulated control muscle; however, aged muscle mitochondria decreased fatty acid oxidation.
In contrast, following LISS, young skeletal muscle decreased fatty acid oxidation, whereas aged muscle
increased fatty acid oxidation. We also found that HII inhibits oxidation of glutamate in both stimulated and non-
stimulated aged muscle, suggesting HII stimulates circulation of a factor capable of altering metabolism
systemically. While longitudinal studies of skeletal muscle function in humans provide invaluable information on
the complex biology of aging and the impact on metabolism, muscle force, and fatiguability, they are often limiting
for mechanistic tests. We have partnered with the Study of Muscle, Mobility and Aging (R01 AG059416) to obtain
primary human myoblasts from well phenotyped older adults to develop a three-dimensional tissue model of
skeletal muscle aging. Developments in tissue engineering using primary cells purified directly from patients offer
some of the best opportunities yet to link specific mechanistic tests of metabolic and muscle function to patient
data. We will adapt our in vivo contraction protocols for in vitro use to test the hypothesis that aging impairs
metabolic response following contraction in human three-dimensional engineered muscle tissue (3D-EMT). We
will test this hypothesis with two specific aims: 1) Examine the mitochondrial mechanisms of decreased metabolic
response to muscle contraction in aged human 3D-EMT and 2) we will characterize the effect of aging on
adaptation to longitudinal contractile training of 3D-EMT in vitro. This proposal will capitalize on the stellar
environment for aging and muscle research at University of Washington (UW). The UW houses a Nathan Shock
Center of Excellence in the Basic Biology of Aging, the Center for Translational Muscle Research, Northwest
Metabolomics Research Center, and the Institute for Stem Cells and Regenerative Medicine. The research team
comprises experts in the fields of muscle mechanics, mitochondrial function, metabolism, and tissue engineering
and uniquely places them in a position to implement the development of this in vitro model and to successfully
test muscle and mitochondrial function.

Grant Number: 1R21AG088504-01
NIH Institute/Center: NIH
Principal Investigator: Matthew Campbell