Scholars@Duke
Timothy Robert Koves

Timothy Robert Koves

Associate Professor in Medicine
Medicine, Geriatrics and Palliative Care
tim.koves@duke.edu
Duke Box 104775, Durham, NC 27704
300 North Duke Street, 50-202 / Carmichael Bldg, Durham, NC 27701

Selected Publications

Bioengineered Model of Human LGMD2B Skeletal Muscle Reveals Roles of Intracellular Calcium Overload in Contractile and Metabolic Dysfunction in Dysferlinopathy.

Journal Article Adv Sci (Weinh) · August 2024 Dysferlin is a multi-functional protein that regulates membrane resealing, calcium homeostasis, and lipid metabolism in skeletal muscle. Genetic loss of dysferlin results in limb girdle muscular dystrophy 2B/2R (LGMD2B/2R) and other dysferlinopathies - rar ... Full text Link to item Cite

Ketone flux through BDH1 supports metabolic remodeling of skeletal and cardiac muscles in response to intermittent time-restricted feeding.

Journal Article Cell Metab · February 6, 2024 Time-restricted feeding (TRF) has gained attention as a dietary regimen that promotes metabolic health. This study questioned if the health benefits of an intermittent TRF (iTRF) schedule require ketone flux specifically in skeletal and cardiac muscles. No ... Full text Link to item Cite

Pyruvate-supported flux through medium-chain ketothiolase promotes mitochondrial lipid tolerance in cardiac and skeletal muscles.

Journal Article Cell metabolism · June 2023 Even-chain acylcarnitine (AC) metabolites, most of which are generated as byproducts of incomplete fatty acid oxidation (FAO), are viewed as biomarkers of mitochondrial lipid stress attributable to one or more metabolic bottlenecks in the β-oxidation pathw ... Full text Cite

Acetyl-CoA carboxylase 1 is a suppressor of the adipocyte thermogenic program.

Journal Article Cell Rep · May 30, 2023 Disruption of adipocyte de novo lipogenesis (DNL) by deletion of fatty acid synthase (FASN) in mice induces browning in inguinal white adipose tissue (iWAT). However, adipocyte FASN knockout (KO) increases acetyl-coenzyme A (CoA) and malonyl-CoA in additio ... Full text Link to item Cite

RIP140 deficiency enhances cardiac fuel metabolism and protects mice from heart failure.

Journal Article J Clin Invest · May 1, 2023 During the development of heart failure (HF), the capacity for cardiomyocyte (CM) fatty acid oxidation (FAO) and ATP production is progressively diminished, contributing to pathologic cardiac hypertrophy and contractile dysfunction. Receptor-interacting pr ... Full text Link to item Cite

Skeletal muscle mitochondrial inertia is associated with carnitine acetyltransferase activity and physical function in humans.

Conference JCI Insight · January 10, 2023 BACKGROUNDAt the onset of exercise, the speed at which phosphocreatine (PCr) decreases toward a new steady state (PCr on-kinetics) reflects the readiness to activate mitochondrial ATP synthesis, which is secondary to Acetyl-CoA availability in skeletal mus ... Full text Link to item Cite

Effects of SGLT2 inhibitor dapagliflozin in patients with type 2 diabetes on skeletal muscle cellular metabolism.

Journal Article Mol Metab · December 2022 OBJECTIVE: SGLT2 inhibitors increase urinary glucose excretion and have beneficial effects on cardiovascular and renal outcomes; the underlying mechanism may be metabolic adaptations due to urinary glucose loss. Here, we investigated the cellular and molec ... Full text Link to item Cite

Chemotherapeutic drug screening in 3D-Bioengineered human myobundles provides insight into taxane-induced myotoxicities.

Journal Article iScience · October 21, 2022 Two prominent frontline breast cancer (BC) chemotherapies commonly used in combination, doxorubicin (DOX) and docetaxel (TAX), are associated with long-lasting cardiometabolic and musculoskeletal side effects. Whereas DOX has been linked to mitochondrial d ... Full text Open Access Link to item Cite

Rheumatoid arthritis T cell and muscle oxidative metabolism associate with exercise-induced changes in cardiorespiratory fitness.

Journal Article Sci Rep · May 6, 2022 Rheumatoid arthritis (RA) T cells drive autoimmune features via metabolic reprogramming that reduces oxidative metabolism. Exercise training improves cardiorespiratory fitness (i.e., systemic oxidative metabolism) and thus may impact RA T cell oxidative me ... Full text Open Access Link to item Cite

Disruption of STIM1-mediated Ca2+ sensing and energy metabolism in adult skeletal muscle compromises exercise tolerance, proteostasis, and lean mass.

Journal Article Mol Metab · March 2022 OBJECTIVE: Stromal interaction molecule 1 (STIM1) is a single-pass transmembrane endoplasmic/sarcoplasmic reticulum (E/SR) protein recognized for its role in a store operated Ca2+ entry (SOCE), an ancient and ubiquitous signaling pathway. Whereas STIM1 is ... Full text Open Access Link to item Cite

Nicotinamide riboside supplementation confers marginal metabolic benefits in obese mice without remodeling the muscle acetyl-proteome.

Journal Article iScience · January 21, 2022 Nicotinamide riboside supplements (NRS) have been touted as a nutraceutical that promotes cardiometabolic and musculoskeletal health by enhancing nicotinamide adenine dinucleotide (NAD+) biosynthesis, mitochondrial function, and/or the activities of NAD-de ... Full text Link to item Cite

Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations.

Journal Article JCI insight · May 2021 Lipin 1 is a bifunctional protein that is a transcriptional regulator and has phosphatidic acid (PA) phosphohydrolase activity, which dephosphorylates PA to generate diacylglycerol. Human lipin 1 mutations lead to episodic rhabdomyolysis, and some affected ... Full text Cite

Muscle-Liver Trafficking of BCAA-Derived Nitrogen Underlies Obesity-Related Glycine Depletion.

Journal Article Cell Rep · November 10, 2020 Glycine levels are inversely associated with branched-chain amino acids (BCAAs) and cardiometabolic disease phenotypes, but biochemical mechanisms that explain these relationships remain uncharted. Metabolites and genes related to BCAA metabolism and nitro ... Full text Link to item Cite

Nutritional modulation of heart failure in mitochondrial pyruvate carrier-deficient mice.

Journal Article Nat Metab · November 2020 The myocardium is metabolically flexible; however, impaired flexibility is associated with cardiac dysfunction in conditions including diabetes and heart failure. The mitochondrial pyruvate carrier (MPC) complex, composed of MPC1 and MPC2, is required for ... Full text Link to item Cite

Extreme Acetylation of the Cardiac Mitochondrial Proteome Does Not Promote Heart Failure.

Journal Article Circ Res · September 25, 2020 RATIONALE: Circumstantial evidence links the development of heart failure to posttranslational modifications of mitochondrial proteins, including lysine acetylation (Kac). Nonetheless, direct evidence that Kac compromises mitochondrial performance remains ... Full text Link to item Cite

Disruption of Acetyl-Lysine Turnover in Muscle Mitochondria Promotes Insulin Resistance and Redox Stress without Overt Respiratory Dysfunction.

Journal Article Cell Metab · January 7, 2020 This study sought to examine the functional significance of mitochondrial protein acetylation using a double knockout (DKO) mouse model harboring muscle-specific deficits in acetyl-CoA buffering and lysine deacetylation, due to genetic ablation of carnitin ... Full text Link to item Cite

Rejuvenation of Neutrophil Functions in Association With Reduced Diabetes Risk Following Ten Weeks of Low-Volume High Intensity Interval Walking in Older Adults With Prediabetes - A Pilot Study.

Journal Article Front Immunol · 2020 Neutrophil dysfunction is a common feature of aging, and is associated with the pathogenesis of many age-related diseases, including type 2 diabetes mellitus (T2DM). Although exercise training improves metabolic health, decreases risk of T2DM, and is assoc ... Full text Link to item Cite

Systematic Dissection of the Metabolic-Apoptotic Interface in AML Reveals Heme Biosynthesis to Be a Regulator of Drug Sensitivity.

Journal Article Cell Metab · May 7, 2019 Crosstalk between metabolic and survival pathways is critical for cellular homeostasis, but the connectivity between these processes remains poorly defined. We used loss-of-function CRISPR/Cas9 knockout screening to identify metabolic genes capable of infl ... Full text Link to item Cite

Electrical stimulation increases hypertrophy and metabolic flux in tissue-engineered human skeletal muscle.

Journal Article Biomaterials · April 2019 In vitro models of contractile human skeletal muscle hold promise for use in disease modeling and drug development, but exhibit immature properties compared to native adult muscle. To address this limitation, 3D tissue-engineered human muscles (myobundles) ... Full text Link to item Cite

Abstract P284: The Chemotherapeutic Agent Docetaxel Disrupts Mitochondrial Energetics in 3D Human Bioengineered Myobundles

Conference Circulation · March 5, 2019 Taxanes (i.e. docetaxel, (TAX)) comprise the first line-treatment for breast cancer (BC), mostly in combination with anthracyclines like doxorubicin (DOX). The efficacy of these drugs as antineoplastic agents has helped to boost 10-yea ... Full text Cite

Respiratory Phenomics across Multiple Models of Protein Hyperacylation in Cardiac Mitochondria Reveals a Marginal Impact on Bioenergetics.

Journal Article Cell Rep · February 5, 2019 Acyl CoA metabolites derived from the catabolism of carbon fuels can react with lysine residues of mitochondrial proteins, giving rise to a large family of post-translational modifications (PTMs). Mass spectrometry-based detection of thousands of acyl-PTMs ... Full text Link to item Cite

A Mitochondrial Progesterone Receptor Increases Cardiac Beta-Oxidation and Remodeling.

Journal Article J Endocr Soc · February 1, 2019 Progesterone is primarily a pregnancy-related hormone, produced in substantial quantities after ovulation and during gestation. Traditionally known to function via nuclear receptors for transcriptional regulation, there is also evidence of nonnuclear actio ... Full text Open Access Link to item Cite

Plasma MicroRNAs in Established Rheumatoid Arthritis Relate to Adiposity and Altered Plasma and Skeletal Muscle Cytokine and Metabolic Profiles.

Journal Article Front Immunol · 2019 Background: MicroRNAs have been implicated in the pathogenesis of rheumatoid arthritis (RA), obesity, and altered metabolism. Although RA is associated with both obesity and altered metabolism, expression of RA-related microRNA in the setting of these card ... Full text Link to item Cite

Mitochondrial Diagnostics: A Multiplexed Assay Platform for Comprehensive Assessment of Mitochondrial Energy Fluxes.

Journal Article Cell Rep · September 25, 2018 Chronic metabolic diseases have been linked to molecular signatures of mitochondrial dysfunction. Nonetheless, molecular remodeling of the transcriptome, proteome, and/or metabolome does not necessarily translate to functional consequences that confer phys ... Full text Link to item Cite

Human, Tissue-Engineered, Skeletal Muscle Myobundles to Measure Oxygen Uptake and Assess Mitochondrial Toxicity.

Journal Article Tissue Eng Part C Methods · April 2017 Mitochondrial dysfunction is responsible for the toxicity of a number of drugs. Current isolated mitochondria or cellular monoculture mitochondrial respiration measurement systems lack physiological relevance. Using a tissue engineering rather than cell- o ... Full text Link to item Cite

Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages.

Journal Article J Biol Chem · March 17, 2017 The immunity-related GTPases (IRGs) are a family of proteins that are induced by interferon (IFN)-γ and play pivotal roles in immune and inflammatory responses. IRGs ostensibly function as dynamin-like proteins that bind to intracellular membranes and prom ... Full text Link to item Cite

Molecular alterations in skeletal muscle in rheumatoid arthritis are related to disease activity, physical inactivity, and disability.

Journal Article Arthritis Res Ther · January 23, 2017 BACKGROUND: To identify molecular alterations in skeletal muscle in rheumatoid arthritis (RA) that may contribute to ongoing disability in RA. METHODS: Persons with seropositive or erosive RA (n = 51) and control subjects matched for age, gender, race, bod ... Full text Open Access Link to item Cite

Plasma acylcarnitines during insulin stimulation in humans are reflective of age-related metabolic dysfunction.

Journal Article Biochem Biophys Res Commun · October 28, 2016 The purpose of this study was to determine if plasma acylcarnitine (AC) profiling is altered under hyperinsulinemic conditions as part of the aging process. Fifteen young, lean (19-29 years) and fifteen middle-to older-aged (57-82 years) individuals underw ... Full text Link to item Cite

The Failing Heart Relies on Ketone Bodies as a Fuel.

Journal Article Circulation · February 23, 2016 BACKGROUND: Significant evidence indicates that the failing heart is energy starved. During the development of heart failure, the capacity of the heart to utilize fatty acids, the chief fuel, is diminished. Identification of alternate pathways for myocardi ... Full text Link to item Cite

Metabolic Catastrophe in Mice Lacking Transferrin Receptor in Muscle.

Journal Article EBioMedicine · November 2015 Transferrin receptor (Tfr1) is ubiquitously expressed, but its roles in non-hematopoietic cells are incompletely understood. We used a tissue-specific conditional knockout strategy to ask whether skeletal muscle required Tfr1 for iron uptake. We found that ... Full text Link to item Cite

Increased palmitate intake: higher acylcarnitine concentrations without impaired progression of β-oxidation.

Journal Article J Lipid Res · September 2015 Palmitic acid (PA) is associated with higher blood concentrations of medium-chain acylcarnitines (MCACs), and we hypothesized that PA may inhibit progression of FA β-oxidation. Using a cross-over design, 17 adults were fed high PA (HPA) and low PA/high ole ... Full text Link to item Cite

Carnitine Acetyltransferase Mitigates Metabolic Inertia and Muscle Fatigue during Exercise.

Journal Article Cell Metab · July 7, 2015 Acylcarnitine metabolites have gained attention as biomarkers of nutrient stress, but their physiological relevance and metabolic purpose remain poorly understood. Short-chain carnitine conjugates, including acetylcarnitine, derive from their corresponding ... Full text Link to item Cite

Metabolomic analysis reveals altered skeletal muscle amino acid and fatty acid handling in obese humans.

Journal Article Obesity (Silver Spring) · May 2015 OBJECTIVE: Investigate the effects of obesity and high-fat diet (HFD) exposure on fatty acid oxidation and TCA cycle intermediates and amino acids in skeletal muscle to better characterize energy metabolism. METHODS: Plasma and skeletal muscle metabolomic ... Full text Link to item Cite

Metabolomic analysis reveals altered skeletal muscle amino acid and fatty acid handling in obese humans

Journal Article Obesity · May 1, 2015 Objective Investigate the effects of obesity and high-fat diet (HFD) exposure on fatty acid oxidation and TCA cycle intermediates and amino acids in skeletal muscle to better characterize energy metabolism. Methods Plasma and skeletal muscle metabolomic pr ... Full text Cite

Compartmentalized acyl-CoA metabolism in skeletal muscle regulates systemic glucose homeostasis.

Journal Article Diabetes · January 2015 The impaired capacity of skeletal muscle to switch between the oxidation of fatty acid (FA) and glucose is linked to disordered metabolic homeostasis. To understand how muscle FA oxidation affects systemic glucose, we studied mice with a skeletal muscle-sp ... Full text Link to item Cite

Metabolite signatures of exercise training in human skeletal muscle relate to mitochondrial remodelling and cardiometabolic fitness.

Journal Article Diabetologia · November 2014 AIMS/HYPOTHESIS: Targeted metabolomic and transcriptomic approaches were used to evaluate the relationship between skeletal muscle metabolite signatures, gene expression profiles and clinical outcomes in response to various exercise training interventions. ... Full text Link to item Cite

Energy metabolic reprogramming in the hypertrophied and early stage failing heart: a multisystems approach.

Journal Article Circ Heart Fail · November 2014 BACKGROUND: An unbiased systems approach was used to define energy metabolic events that occur during the pathological cardiac remodeling en route to heart failure (HF). METHODS AND RESULTS: Combined myocardial transcriptomic and metabolomic profiling were ... Full text Link to item Cite

Long-echo time MR spectroscopy for skeletal muscle acetylcarnitine detection.

Journal Article J Clin Invest · November 2014 Animal models suggest that acetylcarnitine production is essential for maintaining metabolic flexibility and insulin sensitivity. Because current methods to detect acetylcarnitine involve biopsy of the tissue of interest, noninvasive alternatives to measur ... Full text Link to item Cite

Treatment with the 3-ketoacyl-CoA thiolase inhibitor trimetazidine does not exacerbate whole-body insulin resistance in obese mice.

Journal Article J Pharmacol Exp Ther · June 2014 There is a growing need to understand the underlying mechanisms involved in the progression of cardiovascular disease during obesity and diabetes. Although inhibition of fatty acid oxidation has been proposed as a novel approach to treat ischemic heart dis ... Full text Link to item Cite

Obesity and lipid stress inhibit carnitine acetyltransferase activity.

Journal Article J Lipid Res · April 2014 Carnitine acetyltransferase (CrAT) is a mitochondrial matrix enzyme that catalyzes the interconversion of acetyl-CoA and acetylcarnitine. Emerging evidence suggests that this enzyme functions as a positive regulator of total body glucose tolerance and musc ... Full text Link to item Cite

Targeted metabolomics connects thioredoxin-interacting protein (TXNIP) to mitochondrial fuel selection and regulation of specific oxidoreductase enzymes in skeletal muscle.

Journal Article J Biol Chem · March 21, 2014 Thioredoxin-interacting protein (TXNIP) is an α-arrestin family member involved in redox sensing and metabolic control. Growing evidence links TXNIP to mitochondrial function, but the molecular nature of this relationship has remained poorly defined. Herei ... Full text Link to item Cite

Dietary intake of palmitate and oleate has broad impact on systemic and tissue lipid profiles in humans.

Journal Article Am J Clin Nutr · March 2014 BACKGROUND: Epidemiologic evidence has suggested that diets with a high ratio of palmitic acid (PA) to oleic acid (OA) increase risk of cardiovascular disease (CVD). OBJECTIVE: To gain additional insights into the relative effect of dietary fatty acids and ... Full text Link to item Cite

Measurement of fatty acid oxidation rates in animal tissues and cell lines.

Journal Article Methods Enzymol · 2014 While much oncological research has focused on metabolic shifts in glucose and amino acid oxidation, recent evidence suggests that fatty acid oxidation (FAO) may also play an important role in the metabolic reprogramming of cancer cells. Here, we present a ... Full text Link to item Cite

SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase.

Journal Article Mol Cell · June 6, 2013 Lipid metabolism is tightly controlled by the nutritional state of the organism. Nutrient-rich conditions increase lipogenesis, whereas nutrient deprivation promotes fat oxidation. In this study, we identify the mitochondrial sirtuin, SIRT4, as a regulator ... Full text Link to item Cite

A lipidomics analysis of the relationship between dietary fatty acid composition and insulin sensitivity in young adults.

Journal Article Diabetes · April 2013 Relative to diets enriched in palmitic acid (PA), diets rich in oleic acid (OA) are associated with reduced risk of type 2 diabetes. To gain insight into mechanisms underlying these observations, we applied comprehensive lipidomic profiling to specimens co ... Full text Link to item Cite

Substituting dietary monounsaturated fat for saturated fat is associated with increased daily physical activity and resting energy expenditure and with changes in mood.

Journal Article Am J Clin Nutr · April 2013 BACKGROUND: The Western diet increases risk of metabolic disease. OBJECTIVE: We determined whether lowering the ratio of saturated fatty acids to monounsaturated fatty acids in the Western diet would affect physical activity and energy expenditure. DESIGN: ... Full text Link to item Cite

PPARγ coactivator-1α contributes to exercise-induced regulation of intramuscular lipid droplet programming in mice and humans.

Journal Article J Lipid Res · February 2013 Intramuscular accumulation of triacylglycerol, in the form of lipid droplets (LD), has gained widespread attention as a hallmark of metabolic disease and insulin resistance. Paradoxically, LDs also amass in muscles of highly trained endurance athletes who ... Full text Link to item Cite

Ectopic lipid deposition and the metabolic profile of skeletal muscle in ovariectomized mice.

Journal Article Am J Physiol Regul Integr Comp Physiol · February 2013 Disruptions of ovarian function in women are associated with increased risk of metabolic disease due to dysregulation of peripheral glucose homeostasis in skeletal muscle. Our previous evidence suggests that alterations in skeletal muscle lipid metabolism ... Full text Link to item Cite

Design considerations for an integrated microphysiological muscle tissue for drug and tissue toxicity testing.

Journal Article Stem Cell Res Ther · 2013 Microphysiological systems provide a tool to simulate normal and pathological function of organs for prolonged periods. These systems must incorporate the key functions of the individual organs and enable interactions among the corresponding microphysiolog ... Full text Link to item Cite

Identification of a novel malonyl-CoA IC(50) for CPT-I: implications for predicting in vivo fatty acid oxidation rates.

Journal Article Biochem J · November 15, 2012 Published values regarding the sensitivity (IC(50)) of CPT-I (carnitine palmitoyltransferase I) to M-CoA (malonyl-CoA) inhibition in isolated mitochondria are inconsistent with predicted in vivo rates of fatty acid oxidation. Therefore we have re-examined ... Full text Link to item Cite

Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility.

Journal Article Cell Metab · May 2, 2012 The concept of "metabolic inflexibility" was first introduced to describe the failure of insulin-resistant human subjects to appropriately adjust mitochondrial fuel selection in response to nutritional cues. This phenomenon has since gained increasing reco ... Full text Link to item Cite

Re-patterning of skeletal muscle energy metabolism by fat storage-inducing transmembrane protein 2.

Journal Article J Biol Chem · December 9, 2011 Triacylglyceride stored in cytosolic lipid droplets (LDs) constitutes a major energy reservoir in most eukaryotes. The regulated turnover of triacylglyceride in LDs provides fatty acids for mitochondrial β-oxidation and ATP generation in physiological stat ... Full text Link to item Cite

Mouse cardiac acyl coenzyme a synthetase 1 deficiency impairs Fatty Acid oxidation and induces cardiac hypertrophy.

Journal Article Mol Cell Biol · March 2011 Long-chain acyl coenzyme A (acyl-CoA) synthetase isoform 1 (ACSL1) catalyzes the synthesis of acyl-CoA from long-chain fatty acids and contributes the majority of cardiac long-chain acyl-CoA synthetase activity. To understand its functional role in the hea ... Full text Link to item Cite

A high-fat diet elicits differential responses in genes coordinating oxidative metabolism in skeletal muscle of lean and obese individuals.

Journal Article J Clin Endocrinol Metab · March 2011 CONTEXT: In lean individuals, increasing dietary lipid can elicit an increase in whole body lipid oxidation; however, with obesity the capacity to respond to changes in substrate availability appears to be compromised. OBJECTIVE: To determine whether the r ... Full text Link to item Cite

Inhibition of de novo ceramide synthesis reverses diet-induced insulin resistance and enhances whole-body oxygen consumption.

Journal Article Diabetes · October 2010 OBJECTIVE: It has been proposed that skeletal muscle insulin resistance arises from the accumulation of intramyocellular lipid metabolites that impede insulin signaling, including diacylglycerol and ceramide. We determined the role of de novo ceramide synt ... Full text Link to item Cite

Metabolic profiling of muscle contraction in lean compared with obese rodents.

Journal Article Am J Physiol Regul Integr Comp Physiol · September 2010 Interest in the pathophysiological relevance of intramuscular triacylglycerol (IMTG) accumulation has grown from numerous studies reporting that abnormally high glycerolipid levels in tissues of obese and diabetic subjects correlate negatively with glucose ... Full text Link to item Cite

Adipose acyl-CoA synthetase-1 directs fatty acids toward beta-oxidation and is required for cold thermogenesis.

Journal Article Cell Metab · July 7, 2010 Long-chain acyl-CoA synthetase-1 (ACSL1) contributes 80% of total ACSL activity in adipose tissue and was believed to be essential for the synthesis of triacylglycerol. We predicted that an adipose-specific knockout of ACSL1 (Acsl1(A-/-)) would be lipodyst ... Full text Link to item Cite

Alterations in skeletal muscle fatty acid handling predisposes middle-aged mice to diet-induced insulin resistance.

Journal Article Diabetes · June 2010 OBJECTIVE: Although advanced age is a risk factor for type 2 diabetes, a clear understanding of the changes that occur during middle age that contribute to the development of skeletal muscle insulin resistance is currently lacking. Therefore, we sought to ... Full text Link to item Cite

Peroxisome proliferator-activated receptor-gamma coactivator-1alpha overexpression increases lipid oxidation in myocytes from extremely obese individuals.

Journal Article Diabetes · June 2010 OBJECTIVE: To determine whether the obesity-related decrement in fatty acid oxidation (FAO) in primary human skeletal muscle cells (HSkMC) is linked with lower mitochondrial content and whether this deficit could be corrected via overexpression of peroxiso ... Full text Link to item Cite

Liver-specific loss of long chain acyl-CoA synthetase-1 decreases triacylglycerol synthesis and beta-oxidation and alters phospholipid fatty acid composition.

Journal Article J Biol Chem · October 9, 2009 In mammals, a family of five acyl-CoA synthetases (ACSLs), each the product of a separate gene, activates long chain fatty acids to form acyl-CoAs. Because the ACSL isoforms have overlapping preferences for fatty acid chain length and saturation and are ex ... Full text Link to item Cite

Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control.

Journal Article J Biol Chem · August 21, 2009 In addition to its essential role in permitting mitochondrial import and oxidation of long chain fatty acids, carnitine also functions as an acyl group acceptor that facilitates mitochondrial export of excess carbons in the form of acylcarnitines. Recent e ... Full text Link to item Cite

Insulin-stimulated cardiac glucose oxidation is increased in high-fat diet-induced obese mice lacking malonyl CoA decarboxylase.

Journal Article Diabetes · August 2009 OBJECTIVE: Whereas an impaired ability to oxidize fatty acids is thought to contribute to intracellular lipid accumulation, insulin resistance, and cardiac dysfunction, high rates of fatty acid oxidation could also impair glucose metabolism and function. W ... Full text Link to item Cite

Increased insulin sensitivity in mice lacking collectrin, a downstream target of HNF-1alpha.

Journal Article Mol Endocrinol · June 2009 Collectrin is a downstream target of the transcription factor hepatocyte nuclear factor-1alpha (HNF-1alpha), which is mutated in maturity-onset diabetes of the young subtype 3 (MODY3). Evidence from transgenic mouse models with collectrin overexpression in ... Full text Link to item Cite

Metabolic profiling of PPARalpha-/- mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation.

Journal Article FASEB J · February 2009 Peroxisome proliferator-activated receptor-alpha (PPARalpha) is a master transcriptional regulator of beta-oxidation and a prominent target of hypolipidemic drugs. To gain deeper insights into the systemic consequences of impaired fat catabolism, we used q ... Full text Link to item Cite

Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance.

Journal Article Cell Metab · January 2008 Featured Publication Previous studies have suggested that insulin resistance develops secondary to diminished fat oxidation and resultant accumulation of cytosolic lipid molecules that impair insulin signaling. Contrary to this model, the present study used targeted metabolomi ... Full text Link to item Cite

Skeletal muscle adaptation to fatty acid depends on coordinated actions of the PPARs and PGC1 alpha: implications for metabolic disease.

Journal Article Appl Physiol Nutr Metab · October 2007 Featured Publication Dyslipidemia and intramuscular accumulation of fatty acid metabolites are increasingly recognized as core features of obesity and type 2 diabetes. Emerging evidence suggests that normal physiological adaptations to a heavy lipid load depend on the coordina ... Full text Link to item Cite

Contraction of insulin-resistant muscle normalizes insulin action in association with increased mitochondrial activity and fatty acid catabolism.

Journal Article Am J Physiol Cell Physiol · February 2007 Featured Publication Acute exercise can reverse muscle insulin resistance, but the mechanism(s) of action are unknown. With the use of a hindlimb perfusion model, we have found that acute contraction restores insulin-stimulated glucose uptake in muscle of obese Zucker rats to ... Full text Link to item Cite

Lipid-induced metabolic dysfunction in skeletal muscle.

Journal Article Novartis Found Symp · 2007 Featured Publication Insulin resistance is a hallmark of type 2 diabetes and commonly observed in other energy-stressed settings such as obesity, starvation, inactivity and ageing. Dyslipidaemia and 'lipotoxicity'--tissue accumulation of lipid metabolites-are increasingly reco ... Full text Link to item Cite

Receptor-selective coactivators as tools to define the biology of specific receptor-coactivator pairs.

Journal Article Mol Cell · December 8, 2006 Featured Publication In the absence of specific high-affinity agonists and antagonists, it has been difficult to define the target genes and biological responses attributable to many of the orphan nuclear receptors (ONRs). Indeed, it appears that many members of this receptor ... Full text Link to item Cite

Peroxisome proliferator-activated receptor-gamma co-activator 1alpha-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency.

Journal Article J Biol Chem · September 30, 2005 Featured Publication Peroxisome proliferator-activated receptor-gamma co-activator 1alpha (PGC1alpha) is a promiscuous co-activator that plays a key role in regulating mitochondrial biogenesis and fuel homeostasis. Emergent evidence links decreased skeletal muscle PGC1alpha ac ... Full text Link to item Cite

Subsarcolemmal and intermyofibrillar mitochondria play distinct roles in regulating skeletal muscle fatty acid metabolism.

Journal Article Am J Physiol Cell Physiol · May 2005 Featured Publication Skeletal muscle contains two populations of mitochondria that appear to be differentially affected by disease and exercise training. It remains unclear how these mitochondrial subpopulations contribute to fiber type-related and/or training-induced changes ... Full text Link to item Cite

Glucose uptake in muscle cell cultures from endurance-trained men.

Journal Article Med Sci Sports Exerc · April 2005 Featured Publication PURPOSE: To examine noninsulin- (basal) and insulin-mediated glucose uptake in human skeletal muscle cells from endurance-trained and sedentary individuals. METHODS: Muscle biopsies (vastus lateralis) were obtained from competitive, endurance-trained athle ... Full text Link to item Cite

Active involvement of PKC for insulin-mediated rates of muscle protein synthesis in Zucker rats.

Journal Article Am J Physiol Endocrinol Metab · May 2004 A recent report from our group demonstrated that insulin facilitates muscle protein synthesis in obese Zucker rats. The purpose of this study was to determine whether PKC, a probable modulator of insulin signal transduction and/or mRNA translation, has a r ... Full text Link to item Cite

Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance.

Journal Article Nat Med · March 2004 Featured Publication Lipid infusion or ingestion of a high-fat diet results in insulin resistance, but the mechanism underlying this phenomenon remains unclear. Here we show that, in rats fed a high-fat diet, whole-animal, muscle and liver insulin resistance is ameliorated fol ... Full text Link to item Cite

Time-dependent recovery from the effects of 6-hydroxydopamine lesions of the rat nucleus accumbens on cocaine self-administration and the levels of dopamine in microdialysates.

Journal Article Psychopharmacology (Berl) · February 2004 RATIONALE: Neurotoxin induced lesions of dopamine-releasing neurons that innervate the nucleus accumbens (NAcc) alter cocaine self-administration. In addition, elevated extracellular levels of NAcc dopamine (DA) are thought to be central to the biological ... Full text Link to item Cite

Brain neurotransmitter turnover rates during rat intravenous cocaine self-administration.

Journal Article Neuroscience · 2003 The turnover rates of dopamine, norepinephrine, serotonin, aspartate, glutamate and GABA were measured in 27 brain regions of rats self-administering cocaine and in yoked cocaine- and yoked vehicle-infused controls using radioactive pulse-labeling procedur ... Full text Link to item Cite

Evidence of a malonyl-CoA-insensitive carnitine palmitoyltransferase I activity in red skeletal muscle.

Journal Article Am J Physiol Endocrinol Metab · May 2002 Featured Publication Carnitine palmitoyltransferase I (CPT I), which is expressed as two distinct isoforms in liver (alpha) and muscle (beta), catalyzes the rate-limiting step in the transport of fatty acid into the mitochondria. Malonyl-CoA, a potent inhibitor of CPT I, is co ... Full text Link to item Cite

Effect of short-term exercise training on insulin-stimulated PI 3-kinase activity in middle-aged men.

Journal Article Am J Physiol Endocrinol Metab · January 2002 Featured Publication The purpose of this study was to determine whether the improved insulin action with short-term exercise training in middle-aged individuals is associated with enhanced phosphatidylinositol (PI) 3-kinase activity in skeletal muscle. Nine men of ages 50-70 y ... Full text Link to item Cite

Adrenomedullin expression in rat uterus is correlated with plasma estradiol.

Journal Article Am J Physiol Endocrinol Metab · January 2002 Levels of expression of adrenomedullin (AM) in the uterus have been reported to vary with the reproductive cycle. This study examines the relationships among uterine AM mRNA, the stage of the estrous cycle, and circulating estradiol and progesterone in cyc ... Full text Link to item Cite

Relationship between fat-to-fat-free mass ratio and decrements in leg strength after downhill running.

Journal Article J Appl Physiol (1985) · April 2001 The purpose of this study was to determine whether greater body fat mass (FM) relative to lean mass would result in more severe muscle damage and greater decrements in leg strength after downhill running. The relationship between the FM-to-fat-free mass ra ... Full text Link to item Cite

The influence of speed, grade and mass during simulated off road bicycling.

Journal Article Appl Ergon · October 2000 The purpose of this investigation was to examine the effects of bicycle mass, speed, and grade on oxygen consumption (VO2), heart rate (HR), and ratings of perceived exertion (RPE) during a simulated off-road riding paradigm. Nine adult subjects with mean ... Full text Link to item Cite

Sex differences in substrate metabolism and energy homeostasis.

Journal Article Can J Appl Physiol · August 2000 Females differ remarkably from males in the mechanisms that regulate substrate utilization and energy homeostasis. Females appear to be less affected in terms of growth and loss of body tissues when subjected to chronic periods of negative energy balance. ... Full text Link to item Cite

Association between muscle fiber composition and blood pressure levels during exercise in men.

Journal Article Am J Hypertens · June 2000 Normotensive individuals with a magnified blood pressure (BP) level during exercise have an increased risk for developing hypertension. The purpose of this study was to determine if skeletal muscle fiber type is related to the BP level during exercise. Pea ... Full text Link to item Cite

Differences in extracellular dopamine concentrations in the nucleus accumbens during response-dependent and response-independent cocaine administration in the rat.

Journal Article Psychopharmacology (Berl) · September 1997 Studies indicate that nucleus accumbens (NAcc) dopamine neurotransmission is involved in the reinforcing and direct effects of cocaine. The present study was initiated to explore further the relationship of NAcc extracellular dopamine concentrations ([DA]e ... Full text Link to item Cite

Effects of ibogaine on responding maintained by food, cocaine and heroin reinforcement in rats.

Journal Article Psychopharmacology (Berl) · February 1995 The effects of ibogaine (40 and 80 mg/kg, i.p.), an indole alkaloid proposed for the treatment of drug abuse, were determined in three different groups of rats responding under an FR10 schedule of food, cocaine or heroin reinforcement. Ibogaine (80 mg/kg, ... Full text Link to item Cite

Chronic cocaine administration increases CNS tyrosine hydroxylase enzyme activity and mRNA levels and tryptophan hydroxylase enzyme activity levels.

Journal Article J Neurochem · December 1993 Cocaine is an inhibitor of dopamine and serotonin reuptake by synaptic terminals and has potent reinforcing effects that lead to its abuse. Tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) catalyze the rate-limiting steps in dopamine and serotoni ... Full text Link to item Cite