Skeletal muscle atrophy/wasting is a devastating complication of a number of chronic diseases including aging, cancer, diabetes, sepsis, AIDS, chronic obstructive pulmonary disease, chronic heart failure, and cystic fibrosis. Beyond a reduced survival rate, muscle atrophy is also related to poor functional status and health-related quality of life in these and many other conditions such as starvation, immobilization, and disuse. However, effective treatments require insight into the etiology of skeletal muscle atrophy. In our search to identify potential regulatory molecules that play an important role in the acquisition and maintenance of skeletal muscle mass, we have accumulated several lines of evidence that support a key role for TNF-related weak-inducer of apoptosis (TWEAK) in regulation of skeletal muscle mass. These findings include: 1) Exogenous addition of recombinant TWEAK protein inhibits myoblast differentiation;2) Inhibition of TWEAK activity using a blocking peptide promotes differentiated functions of myoblasts;3) TWEAK accelerates degradation of specific muscle proteins in differentiated myoblasts;and 4) Chronic administration of TWEAK in mice reduces body and skeletal muscle weights and induces degradation of muscle proteins suggesting that TWEAK is a powerful muscle wasting molecule. Based on our strong preliminary data we hypothesize that: a) Deletion of TWEAK in mice will cause accretion of skeletal muscle mass and prevent muscle loss in response to aging, tumor growth, and diabetes;and b) TWEAK effects on myogenic cells are mediated through activation of signaling pathways independent of the Fn14 receptor. In this grant, using TWEAK-knockout and transgenic mice, we will evaluate the role and mechanisms of action of TWEAK in skeletal muscle.
Our specific aims are to investigate: I) The consequence of disruption of TWEAK gene on the acquisition and maintenance of skeletal muscle mass under normal and pathological conditions;II) The key cellular processes that TWEAK affects in skeletal muscles;and III) The molecular pathways through which TWEAK regulates acquisition and maintenance of skeletal muscle mass. The successful completion of the propsoed work should provide the first experimental proof for involvement of TWEAK in the regulation of skeletal muscle mass and could lead to identification of TWEAK as a novel molecular target for future development of therapies to prevent muscle loss.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG029623-06
Application #
8032454
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Williams, John
Project Start
2007-02-01
Project End
2012-08-31
Budget Start
2011-02-15
Budget End
2012-08-31
Support Year
6
Fiscal Year
2011
Total Cost
$254,644
Indirect Cost
Name
University of Louisville
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
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Xiong, Guangyan; Hindi, Sajedah M; Mann, Aman K et al. (2017) The PERK arm of the unfolded protein response regulates satellite cell-mediated skeletal muscle regeneration. Elife 6:
Hindi, Lubna; McMillan, Joseph D; Afroze, Dil et al. (2017) Isolation, Culturing, and Differentiation of Primary Myoblasts from Skeletal Muscle of Adult Mice. Bio Protoc 7:
Hindi, Sajedah M; Kumar, Ashok (2016) TRAF6 regulates satellite stem cell self-renewal and function during regenerative myogenesis. J Clin Invest 126:151-68
Gallot, Yann Simon; Hindi, Sajedah M; Mann, Aman K et al. (2016) Isolation, Culture, and Staining of Single Myofibers. Bio Protoc 6:
Bohnert, Kyle R; Gallot, Yann S; Sato, Shuichi et al. (2016) Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia. FASEB J 30:3053-68
Hindi, Sajedah M; Kumar, Ashok (2016) Toll-like receptor signalling in regenerative myogenesis: friend and foe. J Pathol 239:125-8
Sato, Shuichi; Ogura, Yuji; Tajrishi, Marjan M et al. (2015) Elevated levels of TWEAK in skeletal muscle promote visceral obesity, insulin resistance, and metabolic dysfunction. FASEB J 29:988-1002
Ogura, Yuji; Hindi, Sajedah M; Sato, Shuichi et al. (2015) TAK1 modulates satellite stem cell homeostasis and skeletal muscle repair. Nat Commun 6:10123
Tajrishi, Marjan M; Zheng, Timothy S; Burkly, Linda C et al. (2014) The TWEAK-Fn14 pathway: a potent regulator of skeletal muscle biology in health and disease. Cytokine Growth Factor Rev 25:215-25

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