Age-related skeletal muscle atrophy is a debilitating condition that is common in veteran patients. However, it is poorly understood and lacks a therapy. To begin to address this problem, we will study its causes. We hypothesize that a central event in the pathogenesis of age-related muscle atrophy is increased expression of ATF4, an evolutionarily ancient transcription factor that is induced by stress. This hypothesis is based on several lines of evidence from our preliminary studies. First, we and others found that ATF4 mRNA is one of a small number of mRNAs increased by a variety of acute atrophy-inducing stresses (fasting, cancer, diabetes, uremia and muscle denervation). Second, we found that transfection of mouse skeletal muscle with plasmid DNA encoding mouse ATF4 was sufficient to induce myofiber atrophy. Third, we found that reducing skeletal muscle ATF4 expression (by RNA interference targeting ATF4 mRNA) reduced fasting-induced muscle atrophy in mice. Although little is known about the pathogenesis of age-related muscle atrophy, previous work suggest that age-related muscle atrophy involves at least some of the same transcriptional control mechanisms that mediate more acute forms of muscle atrophy (such as fasting-induced atrophy). This consideration leads us to hypothesize that ATF4 may mediate age-related muscle atrophy. Consistent with this idea, we performed an unbiased, global analysis of ATF4-mediated gene expression in mouse skeletal muscle, and found that ATF4 induced five atrophy-associated mRNAs (CDKN1A, GADD45A, PEG3, CSRP3 and ANKRD1). Interestingly, previous work showed CDKN1A and GADD45A mRNAs are highly induced by aging in human and mouse skeletal muscle, and the proteins encoded by these mRNAs are viewed as attractive potential mediators of age-related muscle atrophy. Taken together, our preliminary data suggest a model in which atrophy-inducing stresses (such as aging and fasting) increase skeletal muscle ATF4, which in turn induces CDKN1A, PEG3, GADD45A, CSRP3 and ANKRD1 mRNAs to promote muscle atrophy. If this is true, then ATF4 and its downstream mediators represent potential targets for therapies to prevent or reverse age-related muscle atrophy in veteran patients. We propose two aims to test this model.
In Aim 1, we will test the hypothesis that ATF4 plays an essential role in age-related muscle atrophy. To this end, we have developed several methods to specifically excise the ATF4 gene in mouse skeletal muscle. We will use these methods to determine if constitutive loss of ATF4 prevents age-related muscle atrophy, and to determine if acute loss of ATF4 reverses atrophy in aged mice.
In Aim 2, we will test the hypothesis that the proteins encoded by ATF4-dependent atrophy-associated mRNAs (CDKN1A, GADD45A, PEG3, CSRP3 and ANKRD1) mediate ATF4-dependent atrophy. To test this hypothesis, we will overexpress these proteins in mouse skeletal muscle and determine if they are sufficient to induce skeletal myofiber atrophy. We will also use RNA interference in mouse skeletal muscle to determine if these proteins are required for fasting-mediated skeletal myofiber atrophy. Through these studies, we hope to elucidate central events in age-related muscle atrophy, and thus identify novel therapeutic targets for a disabling condition that affects many veteran patients.

Public Health Relevance

Skeletal muscle wasting is very common in elderly veteran patients. Unfortunately, our current understanding of age-related muscle wasting is poor, and a therapy does not exist. As a result, many elderly veteran patients suffer the effects of muscle wasting, including weakness, falls, prolonged hospitalization, and loss of independent living. To begin to address the enormous burden that muscle wasting places on veteran patients and their families, we will study its causes. We hypothesize that a central cause of muscle wasting is a protein called ATF4, which acts as a switch that turns on genes for muscle wasting. We have developed techniques to rid muscle of ATF4, and will investigate if these prevent and reverse age-related muscle wasting in mice. We will also study the genes that ATF4 regulates, so that we may understand how ATF4 causes muscle wasting. We hope that these studies will allow us to understand the causes of age-related muscle wasting, and identify new approaches for treating it in veteran patients.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX000976-01
Application #
8041996
Study Section
Cellular and Molecular Medicine (CAMM)
Project Start
2011-07-01
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
1
Fiscal Year
2012
Total Cost
Indirect Cost
Name
Iowa City VA Medical Center
Department
Type
DUNS #
028084333
City
Iowa City
State
IA
Country
United States
Zip Code
52245