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Principal Investigator: TROY A HORNBERGER
Organization: UNIVERSITY OF WISCONSIN-MADISON
Fiscal Year: 2024
Award: $373,868
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
Project Summary / Abstract
Mechanical stimuli play a major role in the regulation of skeletal muscle mass, and the maintenance of muscle
mass contributes significantly to disease prevention and quality of life. Although the link between mechanical
signals and the regulation of muscle mass has been recognized for decades, the molecular mechanisms that
drive this process are still not known. Hence, the long-term goal of our research is to define the molecular
events via which mechanical stimuli regulate skeletal muscle mass. The primary objective of this project is to
determine the extent to which changes in the phosphorylation of TRIM28 contribute to the mechanical
regulation of muscle mass. We are focusing on this topic because TRIM28 can control the activity of mTOR (a
kinase that has been widely implicated in the mechanical regulation of muscle mass). A recent study also
identified TRIM28 as a scaffold protein that interacts with key myogenic transcription factors (e.g., Mef2 and
MyoD), and it has been shown that phosphorylation of the S473 residue on TRIM28 can act as a switch that
unleashes the transcriptional activity of Mef2 and MyoD. This is intriguing because alterations in the activity of
MyoD and Mef2 have been widely implicated in the regulation of muscle mass, and a recent phosphoproteomic
analysis from our lab revealed that mechanical stimulation leads to a profound increase in TRIM28(S473)
phosphorylation. Moreover, we discovered that the expression of a S473 phosphomimetic mutant of TRIM28 is
sufficient to induce hypertrophy, and that the hypertrophic effect is dependent on the phosphomimetic
mutation. Combined, these observations led us to our central hypothesis: an increase in TRIM28(S473)
phosphorylation is a fundamental part of the pathway via which mechanical stimuli promote an increase in
muscle mass. To rigorously test this hypothesis, we will first use of a combination of biochemical, molecular
and genetic interventions in mice. Importantly, the mouse-based studies will enable us to: i) gain insight into
the mechanisms via which TRIM28(S473D) induces hypertrophy, and ii) define the role that both myofiber and
satellite cell specific changes in TRIM28(S473) phosphorylation play in mechanical load-induced hypertrophy.
In addition to the mouse-based studies, we will also perform a human trial to determine whether the primary
conclusions from mice can be translated to the human condition. Collectively, the outcomes of this project are
expected to establish TRIM28 as a novel regulator of muscle mass and shed light on some of the basic
mechanisms through which alterations in S473 phosphorylation control its hypertrophic effect. The outcomes
are also expected to reveal the existence of a TRIM28-dependent pathway that not only enables mechanical
stimuli to induce hypertrophy, but also the activation of satellite cell proliferation and fusion. Such outcomes
would not only dramatically advance our understanding of how mechanical stimuli regulate muscle mass, but
they would also create a new landmark for future studies that are aimed at developing a comprehensive
understanding of this highly important process.
Terms: <Aging><Basal Transcription Factor><Basal transcription factor genes><Bed rest><Bedrest><Biochemical><Biogenesis><Biopsy><Cachectic><Cachexia><Cell Communication and Signaling><Cell Growth in Number><Cell Multiplication><Cell Nucleus><Cell Proliferation><Cell Signaling><Cell fusion><Cellular Proliferation><DNA Therapy><Dissociation><Embryonic Muscle Cells><Event><FK506 Binding Protein 12-Rapamycin Associated Protein 1><FKBP12 Rapamycin Complex Associated Protein 1><FRAP1><FRAP1 gene><FRAP2><Fiber><Future><Gene Transcription><Gene Transfer Clinical><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genetic Alteration><Genetic Change><Genetic Intervention><Genetic Transcription><Genetic defect><Goals><Growth><Human><Hypertrophy><Immobilization><Intracellular Communication and Signaling><KO mice><Kinases><Knock-out Mice><Knockout Mice><L-Serine><LacZ><LacZ Genes><Link><Maintenance><Mechanical Stimulation><Mechanics><Mechanistic Target of Rapamycin><Mediating><Mice><Mice Mammals><Modern Man><Molecular><Murine><Mus><Muscle><Muscle Disease><Muscle Disorders><Muscle Tissue><Muscle satellite cell><Muscular Diseases><Muscular Dystrophies><Mutation><Myoblasts><Myodystrophica><Myodystrophy><Myopathic Conditions><Myopathic Diseases and Syndromes><Myopathic disease or syndrome><Myopathy><Nucleus><Null Mouse><Origin of Life><Outcome><Pathway interactions><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Play><Precursor Muscle Cells><Process><Protein Biosynthesis><Protein Phosphorylation><Public Health><QOL><Quality of life><RAFT1><RBCC/TRIM Motif><RNA Expression><Regulation><Reporting><Research><Ribosomal Peptide Biosynthesis><Ribosomal Protein Biosynthesis><Ribosomal Protein Synthesis><Ribosomes><Role><Sampling><Scaffolding Protein><Serine><Signal Transduction><Signal Transduction Systems><Signaling><Skeletal Muscle><TRIM Motif><Testing><Tissue Growth><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Transfection><Translating><Translations><Transphosphorylases><Tripartite Motif><Voluntary Muscle><biological signal transduction><co-repressor><corepressor><disease prevention><disorder prevention><experiment><experimental research><experimental study><experiments><gene co-repressor><gene corepressor><gene repair therapy><gene therapy><gene-based therapy><genetic co-repressor><genetic corepressor><genetic therapy><genome mutation><genomic therapy><insight><mTOR><mammalian target of rapamycin><mechanic><mechanical><mechanical cue><mechanical load><mechanical signal><mechanical stimulus><mimetics><muscle bulk><muscle dystrophy><muscle form><muscle mass><muscular><muscular disorder><mutant><novel><ontogeny><orthopedic freezing><pathway><phospho-proteomics><phosphoproteomics><prevent><preventing><protein synthesis><resistance exercise><resistance training><response><satellite cell><skeletal muscle atrophy><skeletal muscle breakdown><skeletal muscle loss><skeletal muscle protein loss><skeletal muscle wasting><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><transcription factor><translation>