Persistent muscle weakness and physical disability decrease quality of life for millions of Americans. Thesephysicallimitationsarelinkedwithpathologicalaccumulationofinter/intramuscularadiposetissue(IMAT) across numerouspopulations and morbidities. This link combined withthe resistanceofIMAT accumulationto standard diet and exercise remodeling cues points to IMAT as being a persistent and unaddressed clinical problem, likely impeding rehabilitativeefforts to maintain or increase muscle strength. The long-term objective of this research is to leverage our understanding of fat-muscle cross-talk to therapeutically modulate IMAT paracrine signaling to promote muscle growth and regeneration. Recently, IMAT has been identified as a specialized sub-type of fat called beige fat, that can be stimulated to adopt features of brown fat, potentially including the secretion of pro-regenerative factors. It is the primary objective of this proposal to determine the mechanismsofpro-regenerativeactionofbrownfatonmuscleandwhetherthisactioncanbemimickedbyIMAT stimulation. Our central hypothesis is that brown fat promotes muscle regeneration by enhancing myogenic differentiation via paracrine secreted follistatin. To address our hypothesis, our approach will use our novel systemofmouseintermuscularfattransplanttomodelparacrinefat-musclecross-talk.Wewillusethissystem tocontrolthetimingandcompositionofbrownfatsignalingformechanisticexplorationofthecellularresponse during muscle regeneration (aim 1) and the role of follistatin in mediating that response (aim 2). We will also explorethetherapeuticpotentialofmimickingbrownfatparacrinesignalingviastimulationinmouseandhuman IMAT(aim3).Altogether,thesestudieswillbroadenourunderstandingofthebasicbiologyofbrownfatsignaling, thenatureofIMAT-musclecross-talkandthetherapeuticpotentialforstimulatingIMATandotherdepotsofbeige fattoimprovetissuephysiology.

Public Health Relevance

Accumulation of fat within and between muscles is a hallmark of chronic muscle pathology and is thought to contributetopersistentmuscleweaknessandfunctionallimitations.Theseexperimentsaimtodefinethenature oftheinteractionbetweenfatandsatellitecells(thecellularsourceformusclegrowthandregeneration)witha specific focus onthe role of fatphenotype. Knowledge gathered from this work will inform the development of adjuvant therapies targeting fat to improve muscle function and quality of life for the more than 1 million Americansseekingrehabilitativecareforchronicmusclepathology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR075773-01
Application #
9799276
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Boyce, Amanda T
Project Start
2019-07-22
Project End
2024-06-30
Budget Start
2019-07-22
Budget End
2020-06-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Washington University
Department
Other Health Professions
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130