Timothy S. McMillen
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View article: The G256E HCM mutation prolongs cardiac muscle relaxation via altered nucleotide handling
The G256E HCM mutation prolongs cardiac muscle relaxation via altered nucleotide handling Open
Mutations in myosin alter its motor functions in diverse ways by affecting different structural and chemo-mechanical events. Multidisciplinary strategies can be used to understand how varying alterations in motor function converge to commo…
View article: The G256E HCM mutation prolongs relaxation via altered nucleotide handling
The G256E HCM mutation prolongs relaxation via altered nucleotide handling Open
Mutations in myosin alter its motor functions in diverse ways by affecting different structural and chemo-mechanical events. Multidisciplinary strategies can be used to understand how varying alterations in motor function converge to commo…
View article: Molecular mechanisms of altered contraction with the β-myosin R403Q mutation in porcine ventricular muscle and a human stem cell-derived cardiomyocyte model
Molecular mechanisms of altered contraction with the β-myosin R403Q mutation in porcine ventricular muscle and a human stem cell-derived cardiomyocyte model Open
I. ABSTRACT The R403Q mutation in the sarcomere protein beta-myosin heavy chain (β-MHC) is a known genetic cause of hypertrophic cardiomyopathy (HCM), associated with ventricular hypercontractility, impaired relaxation, and cardiac arrhyth…
View article: Expression of full-length dystrophin reverses muscular dystrophy defects in young and old mdx4cv mice
Expression of full-length dystrophin reverses muscular dystrophy defects in young and old mdx4cv mice Open
Gene replacement therapies mediated by adeno-associated viral (AAV) vectors represent a promising approach for treating genetic diseases. However, their modest packaging capacity (~4.7 kb) remains an important constraint and significantly …
View article: Myosin Modulators Mavacamten and Aficamten Inhibit Cardiac Contractility Through Different Mechanisms
Myosin Modulators Mavacamten and Aficamten Inhibit Cardiac Contractility Through Different Mechanisms Open
View article: Myosin modulator Aficamten inhibits force in cardiac muscle by altering myosin’s biochemical activity without changing thick filament structure
Myosin modulator Aficamten inhibits force in cardiac muscle by altering myosin’s biochemical activity without changing thick filament structure Open
Background Inhibiting contractility by targeting cardiac myosin is an effective treatment for patients with hypertrophic cardiomyopathy (HCM). Aficamten is a second in class myosin inhibitor with promising clinical data showing improvement…
View article: Molecular mechanisms of altered contraction with the β-myosin R403Q mutation in porcine ventricular muscle and a human stem cell-derived cardiomyocyte model
Molecular mechanisms of altered contraction with the β-myosin R403Q mutation in porcine ventricular muscle and a human stem cell-derived cardiomyocyte model Open
View article: <sup>13</sup>C stable isotope tracing reveals distinct fatty acid oxidation pathways in proliferative versus oxidative cells
<sup>13</sup>C stable isotope tracing reveals distinct fatty acid oxidation pathways in proliferative versus oxidative cells Open
By using 13 C stable isotope-resolved metabolomics and FA-driven oxygen consumption rate analysis, our study provides novel insights into the fate of FA carbon through β-oxidation and downstream TCA cycle in proliferative and oxidative cel…
View article: Calcium has a direct effect on thick filament activation in porcine myocardium
Calcium has a direct effect on thick filament activation in porcine myocardium Open
Sarcomere activation in striated muscle requires both thin filament–based and thick filament–based activation mechanisms. Recent studies have shown that myosin heads on the thick filaments undergo OFF to ON structural transitions in respon…
View article: Mechanisms of a novel regulatory light chain–dependent cardiac myosin inhibitor
Mechanisms of a novel regulatory light chain–dependent cardiac myosin inhibitor Open
Hypertrophic cardiomyopathy (HCM) is a genetic disease of the heart characterized by thickening of the left ventricle (LV), hypercontractility, and impaired relaxation. HCM is caused primarily by heritable mutations in sarcomeric proteins,…
View article: Split intein-mediated protein trans-splicing to express large dystrophins
Split intein-mediated protein trans-splicing to express large dystrophins Open
View article: MYBPC3-c.772G>A mutation results in haploinsufficiency and altered myosin cycling kinetics in a patient induced stem cell derived cardiomyocyte model of hypertrophic cardiomyopathy
MYBPC3-c.772G>A mutation results in haploinsufficiency and altered myosin cycling kinetics in a patient induced stem cell derived cardiomyocyte model of hypertrophic cardiomyopathy Open
View article: Raising NAD <sup>+</sup> Level Stimulates Short-Chain Dehydrogenase/Reductase Proteins to Alleviate Heart Failure Independent of Mitochondrial Protein Deacetylation
Raising NAD <sup>+</sup> Level Stimulates Short-Chain Dehydrogenase/Reductase Proteins to Alleviate Heart Failure Independent of Mitochondrial Protein Deacetylation Open
BACKGROUND: Strategies to increase cellular NAD + (oxidized nicotinamide adenine dinucleotide) level have prevented cardiac dysfunction in multiple models of heart failure, but molecular mechanisms remain unclear. Little is known about the…
View article: Danicamtiv Increases Myosin Recruitment and Alters Cross-Bridge Cycling in Cardiac Muscle
Danicamtiv Increases Myosin Recruitment and Alters Cross-Bridge Cycling in Cardiac Muscle Open
BACKGROUND: Modulating myosin function is a novel therapeutic approach in patients with cardiomyopathy. Danicamtiv is a novel myosin activator with promising preclinical data that is currently in clinical trials. While it is known that dan…
View article: Correction: Heterogeneous expression of CFTR in insulin-secreting β-cells of the normal human islet
Correction: Heterogeneous expression of CFTR in insulin-secreting β-cells of the normal human islet Open
[This corrects the article DOI: 10.1371/journal.pone.0242749.].
View article: Branched-chain keto acids inhibit mitochondrial pyruvate carrier and suppress gluconeogenesis in hepatocytes
Branched-chain keto acids inhibit mitochondrial pyruvate carrier and suppress gluconeogenesis in hepatocytes Open
View article: Danicamtiv increases myosin recruitment and alters the chemomechanical cross bridge cycle in cardiac muscle
Danicamtiv increases myosin recruitment and alters the chemomechanical cross bridge cycle in cardiac muscle Open
Modulating myosin function is a novel therapeutic approach in patients with cardiomyopathy. Detailed mechanism of action of these agents can help predict potential unwanted affects and identify patient populations that can benefit most fro…
View article: Structural OFF/ON transitions of myosin in relaxed porcine myocardium predict calcium-activated force
Structural OFF/ON transitions of myosin in relaxed porcine myocardium predict calcium-activated force Open
Contraction in striated muscle is initiated by calcium binding to troponin complexes, but it is now understood that dynamic transition of myosin between resting, ordered OFF states on thick filaments and active, disordered ON states that c…
View article: Correcting dilated cardiomyopathy with fibroblast-targeted p38 deficiency
Correcting dilated cardiomyopathy with fibroblast-targeted p38 deficiency Open
Inherited mutations in contractile and structural genes, which decrease cardiomyocyte tension generation, are principal drivers of dilated cardiomyopathy (DCM)– the leading cause of heart failure 1,2 . Progress towards developing precision…
View article: RETRACTED: dATP elevation induces myocardial metabolic remodeling to support improved cardiac function
RETRACTED: dATP elevation induces myocardial metabolic remodeling to support improved cardiac function Open
View article: dATP Elevation Induces Myocardial Metabolic Remodeling to Support Improved Cardiac Function
dATP Elevation Induces Myocardial Metabolic Remodeling to Support Improved Cardiac Function Open
Hallmark features of systolic heart failure are reduced contractility and impaired metabolic flexibility of the myocardium. Cardiomyocytes (CMs) with elevated deoxy ATP (dATP) via overexpression of ribonucleotide reductase (RNR) enzyme rob…
View article: X-ray diffraction patterns of the effects of dATP on permeabilized porcine myocardium
X-ray diffraction patterns of the effects of dATP on permeabilized porcine myocardium Open
X-ray and mechanical experiments were performed using permeabilized porcine left ventricle wall muscle. The frozen muscle was thawed in skinning solution at room temperature before dissection into smaller strips and skinned at room tempera…
View article: X-ray diffraction patterns of the effects of dATP on permeabilized porcine myocardium
X-ray diffraction patterns of the effects of dATP on permeabilized porcine myocardium Open
X-ray and mechanical experiments were performed using permeabilized porcine left ventricle wall muscle. The frozen muscle was thawed in skinning solution at room temperature before dissection into smaller strips and skinned at room tempera…
View article: Upregulation of mitochondrial ATPase inhibitory factor 1 (ATPIF1) mediates increased glycolysis in mouse hearts
Upregulation of mitochondrial ATPase inhibitory factor 1 (ATPIF1) mediates increased glycolysis in mouse hearts Open
In hypertrophied and failing hearts, fuel metabolism is reprogrammed to increase glucose metabolism, especially glycolysis. This metabolic shift favors biosynthetic function at the expense of ATP production. Mechanisms responsible for the …
View article: Branched-Chain Keto Acid Inhibits Mitochondrial Pyruvate Carrier and Suppresses Gluconeogenesis
Branched-Chain Keto Acid Inhibits Mitochondrial Pyruvate Carrier and Suppresses Gluconeogenesis Open
View article: Increasing fatty acid oxidation elicits a sex-dependent response in failing mouse hearts
Increasing fatty acid oxidation elicits a sex-dependent response in failing mouse hearts Open
View article: The Progression of Dystrophin-Deficient Dilated Cardiomyopathy through Mechanical and Ca2+ Dysfunction in a Duchenne Muscular Dystrophy Rat Model
The Progression of Dystrophin-Deficient Dilated Cardiomyopathy through Mechanical and Ca2+ Dysfunction in a Duchenne Muscular Dystrophy Rat Model Open
View article: Heterogeneous expression of CFTR in insulin-secreting β-cells of the normal human islet
Heterogeneous expression of CFTR in insulin-secreting β-cells of the normal human islet Open
Cystic fibrosis (CF) is due to mutations in the CF-transmembrane conductance regulator ( CFTR ) and CF-related diabetes (CFRD) is its most common co-morbidity, affecting ~50% of all CF patients, significantly influencing pulmonary function…
View article: Enhancing fatty acid oxidation negatively regulates PPARs signaling in the heart
Enhancing fatty acid oxidation negatively regulates PPARs signaling in the heart Open
View article: Two Small Molecule Inhibitors of Myosin Decrease Force and Increase Rates of Relaxation in Demembranated Rat Left Ventricular Tissue
Two Small Molecule Inhibitors of Myosin Decrease Force and Increase Rates of Relaxation in Demembranated Rat Left Ventricular Tissue Open