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Principal Investigator: Jeffery D Molkentin
Organization: CINCINNATI CHILDRENS HOSP MED CTR
Fiscal Year: 2024
Award: $595,777
Funding agency: National Heart Lung and Blood Institute
Abstract
Like skeletal muscle myofibers, cardiomyocytes in the heart constantly adjust their size based on
perceived workload or disease stimulation, in which hypertrophic versus atrophic pathways are in
balance to achieve an appropriate equilibrium matched to real-time workloads. In a less
appreciated process, both heart and skeletal muscle can reduce size through molecular
regulatory pathways that cause tissue catabolism. This reduction in size is referred to as atrophy
and this process can underlie tissue remodeling and responses to disease stimulation or loss of
sufficient nutrients (such as starvation) in which both tissues can serve as metabolic reservoirs.
Here we uncovered a novel function for thrombospondin1 as a regulator of both cardiac and
skeletal muscle atrophy. We have previously shown that the thrombospondin gene family (Thbs1-
5) plays a critical role in membrane stability through effects on the ER stress response and
secretory pathways, as well as controlling the integrin and dystrophin-glycoprotein complexes
present with the sarcolemma. However, more recently we have discovered that Thbs1 is uniquely
induced by disease stimuli associated with cardiac remodeling and caloric restriction, and that
Thbs1 uniquely regulates cellular atrophy and autophagy through an intracellular pathway within
the ER/SR that functions at 2 levels. 1) Thbs1 directly binds and regulates the ER stress factor
PERK and eIF2α to mediate cardiomyocyte atrophy through the transcription factor ATF4, and 2)
Thbs1 selectively expands lysosomes and the vesicular pathway of autophagy. Hence, we
hypothesize that Thbs1 is an ER-dependent chaperone that mediates cardiomyocyte size
reduction, in part, by driving the catabolic process through autophagy. To investigate this
hypothesis, we will interrogate 2 specific aims: 1) To examine the mechanisms of cardiac atrophy
and autophagy through PERK/eIF2α/ATF4 signaling mediated by Thbs1 within the ER
compartment. 2) To examine a mechanism whereby cardiac autophagy is mediated by Thbs1-
dependent formation of lysosomes and associated catabolic vesicular activity. The proposed
course of investigation will be conducted in both cultured cardiomyocytes and in genetically
modified mouse models so that both reductionist and mechanistic approaches can be taken, as
well as in vivo assessment in a physiologically relevant context. The proposed application is
innovative as it will define for the first time what appears to be a novel cell biology pathway through
Thbs1 that controls striated muscle remodeling through atrophy and autophagy.
Terms: <14-Hydroxydaunomycin><21+ years old><Acute><Adriamycine><Adult><Adult Human><Affect><Anorexia><Assay><Atrophic><Atrophy><Automobile Driving><Autophagocytosis><Autophagosome><Basal Transcription Factor><Basal transcription factor genes><Bed rest><Bedrest><Binding><Bioassay><Biological><Biological Assay><Biological Function><Biological Process><Biotin><Blood Platelets><Body Tissues><CD107b antigen><Calcium Binding><Caloric Restriction><Cancer Cachexia><Cardiac><Cardiac Diseases><Cardiac Disorders><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cardiomyopathies><Catabolic Process><Catabolism><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell-Extracellular Matrix><Cells><Cellular biology><Chaperone><Complex><Data><Disease><Disorder><Doxorubicin><Doxorubicina><Dystrophin><ECM><EIF-2 alpha><EIF-2alpha><EIF-2α><ER stress><Endoplasmic Reticulum><Equilibrium><Ergastoplasm><Expression Signature><Extracellular Matrix><Extracellular Matrix Proteins><Family><Family member><Gene Expression Profile><Gene Family><Gene Modified><Gene Targeting><Gene Transcription><Gene Transfer><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Transcription><Glycoproteins><Heart><Heart Diseases><Heart Hypertrophy><Heart Injuries><Heart Muscle Cells><Heart failure><Heart myocyte><Hydroxyl Daunorubicin><Hydroxyldaunorubicin><Immune Precipitation><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Immunoprecipitation><Injury><Integrins><Integrins Extracellular Matrix><Intracellular Communication and Signaling><Investigation><KO mice><Knock-out Mice><Knockout Mice><LAMP-2><Ligase><Ligase Gene><Location><Lysosomes><Malnutrition><Mammalia><Mammals><Marrow platelet><Mediating><Medical><Membrane><Messenger RNA><Metabolic><Mice><Mice Mammals><Molecular><Molecular Chaperones><Molecular Interaction><Movement><Murine><Mus><Mutant Strains Mice><Myocardial Diseases><Myocardial Disorder><Myocardiopathies><Myocardium><Neonatal><Nodal><Null Mouse><Nutrient><Nutritional Deficiency><Paper><Pathologic><Pathway interactions><Patients><Physiologic><Physiological><Platelets><Play><Process><Protein Glycosylation><Protein Secretion><Proteins><RNA Expression><Regulation><Regulatory Pathway><Role><Sarcolemma><Secretory Granules><Secretory Vesicles><Series><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Skeletal Muscle><Staining method><Stains><Starvation><Stimulus><Stress><Striated Muscles><Synthetases><TSP-1><TSP1><Testing><Thrombocytes><Thrombospondin 1><Thrombospondins><Time><Tissues><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Transgenic Mice><Undernutrition><Ventricle Remodeling><Ventricular Cardiac Remodeling><Ventricular Myocardial Remodeling><Ventricular Remodeling><Vesicle><Vitamin H><Voluntary Muscle><Work><Work Load><Workload><adenoviral mediated><adenovirus-mediated><adulthood><alpha Subunit Eukaryotic Initiation Factor 2><autophagy><balance><balance function><biologic><biological adaptation to stress><biological signal transduction><body movement><calcium bound><caloric restricted><calorically restricted><calorie restricted><calorie restriction><cancer associated cachexia><cancer induced cachexia><cancer-associated muscle wasting><cancer-induced muscle atrophy><cancer-induced muscle loss><cancer-induced muscle wasting><cancer-related cachexia><cardiac failure><cardiac hypertrophy><cardiac injury><cardiac muscle><cardiomyocyte><cell biology><coenzyme R><dietary deficiency><driving><endoplasmic reticulum stress><gene expression pattern><gene expression signature><gene modification><genetically modified><healing><heart disorder><heart muscle><in vivo><injuries><innovate><innovation><innovative><mRNA><malnourished><membrane structure><mortality><mouse model><mouse mutant><murine model><myocardial remodeling><myocardium disease><myocardium disorder><neonatal mice><novel><nutrition deficiency><nutrition deficiency disorder><nutritional deficiency disorder><overexpress><overexpression><pathway><pressure><reaction; crisis><response><skeletal muscle atrophy><skeletal muscle breakdown><skeletal muscle loss><skeletal muscle protein loss><skeletal muscle wasting><social role><stress response><stress; reaction><transcription factor><transcriptional profile><transcriptional signature><tumor-induced cachexia><tumor-induced muscle wasting>