Scholars@Duke
Robert Sanders Williams

Robert Sanders Williams

Professor of Medicine
Medicine, Cardiology
r.s.williams@duke.edu
Box 104775, 300 N Duke St, Durham, NC 27701
300 N Duke St, Durham, NC 27701

Selected Publications

Exercise and health: can biotechnology confer similar benefits?

Journal Article PLoS Med · March 2005 Education and public policies are largely failing to encourage people to exercise. Could our knowledge of exercise biology lead to pharmaceutical treaments that could confer the same benefits as exercise? ... Full text Link to item Cite

Conditional expression of SV40 T-antigen in mouse cardiomyocytes facilitates an inducible switch from proliferation to differentiation.

Journal Article J Biol Chem · May 2, 2003 Studies of cardiac muscle gene expression and signaling have been hampered by the lack of immortalized cardiomyocyte cell lines capable of proliferation and irreversible withdrawal from the cell cycle. With the goal of creating such cell lines, we generate ... Full text Link to item Cite

Personalized health planning.

Journal Article Science · April 25, 2003 Featured Publication Full text Link to item Cite

Highly coordinated gene regulation in mouse skeletal muscle regeneration.

Journal Article J Biol Chem · March 7, 2003 Mammalian skeletal muscles are capable of regeneration after injury. Quiescent satellite cells are activated to reenter the cell cycle and to differentiate for repair, recapitulating features of myogenesis during embryonic development. To understand better ... Full text Link to item Cite

Alterations in slow-twitch muscle phenotype in transgenic mice overexpressing the Ca2+ buffering protein parvalbumin.

Journal Article J Physiol · March 1, 2003 The purpose of this study was to determine whether induced expression of the Ca2+ buffering protein parvalbumin (PV) in slow-twitch fibres would lead to alterations in physiological, biochemical and molecular properties reflective of a fast fibre phenotype ... Full text Link to item Cite

Dual roles of modulatory calcineurin-interacting protein 1 in cardiac hypertrophy.

Journal Article Proc Natl Acad Sci U S A · January 21, 2003 Featured Publication The calcium/calmodulin-dependent protein phosphatase calcineurin stimulates cardiac hypertrophy in response to numerous stimuli. Calcineurin activity is suppressed by association with modulatory calcineurin-interacting protein (MCIP)1DSCR1, which is up-reg ... Full text Link to item Cite

The role of modulatory calcineurin-interacting proteins in calcineurin signaling.

Journal Article Trends Cardiovasc Med · January 2003 Featured Publication Modulatory calcineurin-interacting proteins (MCIPs), also known as the Down syndrome critical region 1 (DSCR1) and DSCR1-like proteins, are a recently described family of small, structurally related proteins that are preferentially expressed in heart, skel ... Full text Link to item Cite

Another surprise from the mitochondrial genome.

Journal Article N Engl J Med · August 22, 2002 Featured Publication Full text Link to item Cite

Multiple domains of MCIP1 contribute to inhibition of calcineurin activity.

Journal Article J Biol Chem · August 16, 2002 Featured Publication Calcineurin is a serine/threonine protein phosphatase that plays a critical role in many physiologic processes such as T-cell activation, apoptosis, skeletal myocyte differentiation, and cardiac hypertrophy. Calcineurin-dependent signals are transduced to ... Full text Link to item Cite

Calcineurin signaling in human cardiac hypertrophy.

Journal Article Circulation · May 14, 2002 Featured Publication Full text Link to item Cite

Regulation of mitochondrial biogenesis in skeletal muscle by CaMK.

Journal Article Science · April 12, 2002 Featured Publication Endurance exercise training promotes mitochondrial biogenesis in skeletal muscle and enhances muscle oxidative capacity, but the signaling mechanisms involved are poorly understood. To investigate this adaptive process, we generated transgenic mice that se ... Full text Link to item Cite

Targeted inhibition of calcineurin in pressure-overload cardiac hypertrophy. Preservation of systolic function.

Journal Article J Biol Chem · March 22, 2002 Featured Publication Calcineurin is a Ca(2+)/calmodulin-activated protein phosphatase that transduces hypertrophic stimuli to regulate transcriptional control of myocyte transformation. It is not known whether overexpression of MCIP1, a recently described endogenous inhibitor ... Full text Link to item Cite

Nerve activity-dependent modulation of calcineurin signaling in adult fast and slow skeletal muscle fibers.

Journal Article J Biol Chem · November 30, 2001 This study tested the hypothesis that calcineurin signaling is modulated in skeletal muscle cells by fluctuations in nerve-mediated activity. We show that dephosphorylation of NFATc1, MEF2A, and MEF2D transcription factors by calcineurin in all muscle type ... Full text Link to item Cite

Activation of MEF2 by muscle activity is mediated through a calcineurin-dependent pathway.

Journal Article EMBO J · November 15, 2001 Featured Publication Gene expression in skeletal muscles of adult vertebrates is altered profoundly by changing patterns of contractile work. Here we observed that the functional activity of MEF2 transcription factors is stimulated by sustained periods of endurance exercise or ... Full text Link to item Cite

Functional and molecular adaptations in skeletal muscle of myoglobin-mutant mice.

Journal Article Am J Physiol Cell Physiol · November 2001 Myoglobin is a cytoplasmic hemoprotein that is restricted to cardiomyocytes and oxidative skeletal myofibers and facilitates oxygen delivery during periods of high metabolic demand. Myoglobin content in skeletal muscle increases in response to hypoxic cond ... Full text Link to item Cite

Cardiac-specific LIM protein FHL2 modifies the hypertrophic response to beta-adrenergic stimulation.

Journal Article Circulation · June 5, 2001 BACKGROUND: A deficiency of muscle LIM protein results in dilated cardiomyopathy, but the function of other LIM proteins in the heart has not been assessed previously. We have characterized the expression and function of FHL2, a heart-specific member of th ... Full text Link to item Cite

Regulatory elements governing transcription in specialized myofiber subtypes.

Journal Article J Biol Chem · May 18, 2001 Skeletal myofibers of vertebrates acquire specialized metabolic and physiological properties as a consequence of developmental cues in the embryo and different patterns of contractile activity in the adult. The myoglobin gene is regulated stringently in mu ... Full text Link to item Cite

Adaptive mechanisms that preserve cardiac function in mice without myoglobin.

Journal Article Circ Res · April 13, 2001 Mice lacking myoglobin survive to adulthood and meet the circulatory demands of exercise and pregnancy without cardiac decompensation. In the present study, we show that many myoglobin-deficient embryos die in utero at midgestation with signs of cardiac fa ... Full text Link to item Cite

Myocyte-enriched calcineurin-interacting protein, MCIP1, inhibits cardiac hypertrophy in vivo.

Journal Article Proc Natl Acad Sci U S A · March 13, 2001 Featured Publication Signaling events controlled by calcineurin promote cardiac hypertrophy, but the degree to which such pathways are required to transduce the effects of various hypertrophic stimuli remains uncertain. In particular, the administration of immunosuppressive dr ... Full text Link to item Cite

Independent signals control expression of the calcineurin inhibitory proteins MCIP1 and MCIP2 in striated muscles.

Journal Article Circ Res · December 8, 2000 Calcineurin, a calcium/calmodulin-regulated protein phosphatase, modulates gene expression in cardiac and skeletal muscles during development and in remodeling responses such as cardiac hypertrophy that are evoked by environmental stresses or disease. Rece ... Full text Link to item Cite

A CDC6 protein-binding peptide selected using a bacterial two-hybrid-like system is a cell cycle inhibitor.

Journal Article J Biol Chem · October 13, 2000 Peptides or small molecules able to modulate protein-protein interactions hold promise as tools with which to probe and manipulate biological pathways. An important issue in this nascent field is to evaluate different methods with which to search libraries ... Full text Link to item Cite

Protective responses in the ischemic myocardium.

Journal Article J Clin Invest · October 2000 Full text Link to item Cite

Repeat polymorphisms within gene regions: phenotypic and evolutionary implications.

Journal Article Am J Hum Genet · August 2000 We have developed an algorithm that predicted 11,265 potentially polymorphic tandem repeats within transcribed sequences. We estimate that 22% (2,207/9,717) of the annotated clusters within UniGene contain at least one potentially polymorphic locus. Our pr ... Full text Link to item Cite

Calcineurin signaling and muscle remodeling.

Journal Article Cell · June 23, 2000 Featured Publication Full text Link to item Cite

Life without myoglobin.

Journal Article Cell Mol Life Sci · June 2000 Hemoproteins are widely distributed among prokaryotes, unicellular eukaryotes, plants and animals [1]. Myoglobin, a cytoplasmic hemoprotein that is restricted to cardiomyocytes and oxidative skeletal myofibers in vertebrates, has been proposed to facilitat ... Full text Link to item Cite

Remodeling muscles with calcineurin.

Journal Article Bioessays · June 2000 Ca(2+) signaling plays a central role in hypertrophic growth of cardiac and skeletal muscle in response to mechanical load and a variety of signals. However, the mechanisms whereby alterations in Ca(2+) in the cytoplasm activate the hypertrophic response a ... Full text Link to item Cite

Cytochrome c deficiency causes embryonic lethality and attenuates stress-induced apoptosis.

Journal Article Cell · May 12, 2000 Featured Publication Cytochrome c released from mitochondria has been proposed to be an essential component of an apoptotic pathway responsive to DNA damage and other forms of cell stress. Murine embryos devoid of cytochrome c die in utero by midgestation, but cell lines estab ... Full text Link to item Cite

Myogenic stem cell function is impaired in mice lacking the forkhead/winged helix protein MNF.

Journal Article Proc Natl Acad Sci U S A · May 9, 2000 Featured Publication Myocyte nuclear factor (MNF) is a winged helix transcription factor that is expressed selectively in myogenic stem cells (satellite cells) of adult animals. Using a gene knockout strategy to generate a functional null allele at the Mnf locus, we observed t ... Full text Link to item Cite

MEF2 responds to multiple calcium-regulated signals in the control of skeletal muscle fiber type.

Journal Article EMBO J · May 2, 2000 Featured Publication Different patterns of motor nerve activity drive distinctive programs of gene transcription in skeletal muscles, thereby establishing a high degree of metabolic and physiological specialization among myofiber subtypes. Recently, we proposed that the influe ... Full text Link to item Cite

A protein encoded within the Down syndrome critical region is enriched in striated muscles and inhibits calcineurin signaling.

Journal Article J Biol Chem · March 24, 2000 Featured Publication Here we describe a small family of proteins, termed MCIP1 and MCIP2 (for myocyte-enriched calcineurin interacting protein), that are expressed most abundantly in striated muscles and that form a physical complex with calcineurin A. MCIP1 is encoded by DSCR ... Full text Link to item Cite

Transgenic animals in integrative biology: approaches and interpretations of outcome.

Journal Article J Appl Physiol (1985) · March 2000 Technological innovations in methods for genetic manipulation of laboratory animals and in techniques for assessment of cardiovascular, respiratory, behavioral, and metabolic physiology in mouse models afford unprecedented opportunities for research in int ... Full text Link to item Cite

Stimulation of slow skeletal muscle fiber gene expression by calcineurin in vivo.

Journal Article J Biol Chem · February 18, 2000 Adult skeletal muscle fibers can be categorized into fast and slow twitch subtypes based on specialized contractile and metabolic properties and on distinctive patterns of muscle gene expression. Muscle fiber-type characteristics are dependent on the frequ ... Full text Link to item Cite

PR48, a novel regulatory subunit of protein phosphatase 2A, interacts with Cdc6 and modulates DNA replication in human cells.

Journal Article Mol Cell Biol · February 2000 Initiation of DNA replication in eukaryotes is dependent on the activity of protein phosphatase 2A (PP2A), but specific phosphoprotein substrates pertinent to this requirement have not been identified. A novel regulatory subunit of PP2A, termed PR48, was i ... Full text Link to item Cite

Electrical stimulation of neonatal cardiac myocytes activates the NFAT3 and GATA4 pathways and up-regulates the adenylosuccinate synthetase 1 gene.

Journal Article J Biol Chem · January 21, 2000 Electrically stimulated pacing of cultured cardiomyocytes serves as an experimentally convenient and physiologically relevant in vitro model of cardiac hypertrophy. Electrical pacing triggers a signaling cascade that results in the activation of the muscle ... Full text Link to item Cite

The winged-helix/forkhead protein myocyte nuclear factor beta (MNF-beta) forms a co-repressor complex with mammalian sin3B.

Journal Article Biochem J · January 15, 2000 Winged-helix/forkhead proteins regulate developmental events in both invertebrate and vertebrate organisms, but biochemical functions that establish a mechanism of action have been defined for only a few members of this extensive gene family. Here we demon ... Link to item Cite

Apoptosis and heart failure.

Journal Article N Engl J Med · September 2, 1999 Full text Link to item Cite

Cell cycle control in the terminally differentiated myocyte. A platform for myocardial repair?

Journal Article Cardiol Clin · November 1998 Currently available pharmaceuticals exert beneficial effects on morbidity and mortality in heart failure. Only cardiac transplantation, however, provides a definitive solution to the irreversible loss of cardiomyocytes in the failing heart. The limited ava ... Full text Link to item Cite

Mice without myoglobin.

Journal Article Nature · October 29, 1998 Featured Publication Myoglobin, an intracellular haemoprotein expressed in the heart and oxidative skeletal myofibres of vertebrates, binds molecular oxygen and may facilitate oxygen transport from erythrocytes to mitochondria, thereby maintaining cellular respiration during p ... Full text Link to item Cite

Collaborative interactions between MEF-2 and Sp1 in muscle-specific gene regulation.

Journal Article J Cell Biochem · September 1, 1998 Previous investigations have demonstrated synergistic interactions in vivo between CCAC and A/T-rich nucleotide sequence motifs as functional components of muscle-specific transcriptional enhancers. Using CCAC and A/T-rich elements from the myoglobin and m ... Link to item Cite

A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type.

Journal Article Genes Dev · August 15, 1998 Featured Publication Slow- and fast-twitch myofibers of adult skeletal muscles express unique sets of muscle-specific genes, and these distinctive programs of gene expression are controlled by variations in motor neuron activity. It is well established that, as a consequence o ... Full text Link to item Cite

E2F3 activity is regulated during the cell cycle and is required for the induction of S phase.

Journal Article Genes Dev · July 15, 1998 Previous work has demonstrated the important role of E2F transcription activity in the induction of S phase during the transition from quiescence to proliferation. In addition to the E2F-dependent activation of a number of genes encoding DNA replication ac ... Full text Link to item Cite

Cdc6 is regulated by E2F and is essential for DNA replication in mammalian cells.

Journal Article Proc Natl Acad Sci U S A · March 31, 1998 Cdc6 has a critical regulatory role in the initiation of DNA replication in yeasts, but its function in mammalian cells has not been characterized. We show here that Cdc6 is expressed selectively in proliferating but not quiescent mammalian cells, both in ... Full text Link to item Cite

Differential expression of mitochondrial DNA replication factors in mammalian tissues.

Journal Article J Biol Chem · February 6, 1998 Mitochondrial biogenesis and mitochondrial DNA (mtDNA) replication are regulated during development and in response to physiological stresses, but the regulatory events that control the abundance of mtDNA in cells of higher eukaryotes have not been defined ... Full text Link to item Cite

Transient regulation of c-fos, alpha B-crystallin, and hsp70 in muscle during recovery from contractile activity.

Journal Article Am J Physiol · February 1998 Endurance exercise training increases the oxidative capacity of skeletal muscles, reflecting the induction of genes encoding enzymes of intermediary metabolism. To test the hypothesis that changes in gene expression may be triggered specifically during rec ... Full text Link to item Cite

Heat shock proteins and ischemic injury to the myocardium.

Journal Article Circulation · December 16, 1997 Link to item Cite

Transient expression of a winged-helix protein, MNF-beta, during myogenesis.

Journal Article Mol Cell Biol · September 1997 A novel winged-helix transcription factor, MNF-beta, is expressed coincidentally with cell cycle withdrawal and differentiation of skeletal myogenic cells. MNF-beta is closely related to the myocyte nuclear factor (MNF) protein previously described (now te ... Full text Link to item Cite

Persistent expression of MNF identifies myogenic stem cells in postnatal muscles.

Journal Article Dev Biol · August 15, 1997 Skeletal muscles contain an undifferentiated myogenic stem cell pool (satellite cells) that can be mobilized to regenerate myofibers in response to injury. We have determined that the winged helix transcription factor MNF is expressed selectively in quiesc ... Full text Link to item Cite

Tetramerization and single-stranded DNA binding properties of native and mutated forms of murine mitochondrial single-stranded DNA-binding proteins.

Journal Article J Biol Chem · March 28, 1997 We examined previously unexplored aspects of the tetramerization and single-stranded DNA (ssDNA) binding properties of native, precursor, and mutated forms of mitochondrial ssDNA-binding protein (mtSSB) from a mammalian organism (mouse). Tetramic forms of ... Full text Link to item Cite

A human protein related to yeast Cdc6p.

Journal Article Proc Natl Acad Sci U S A · January 7, 1997 The unstable proteins Cdc6p and cdc18+ are essential and rate limiting for the initiation of DNA replication in Saccharomyces cerevisiae and Schizosaccharomyces pombe, respectively, and also participate in checkpoint controls that ensure DNA replication is ... Full text Link to item Cite

Continuous contractile activity induces fiber type specific expression of HSP70 in skeletal muscle.

Journal Article Am J Physiol · December 1996 Continuous contractile activity of skeletal muscle elicits an early and dramatic increase in ribosomal RNA, suggesting that translational efficiency and/or capacity is enhanced during the adaptive response to increased metabolic demand. In view of the impo ... Full text Link to item Cite

Cardioprotective effects of 70-kDa heat shock protein in transgenic mice.

Journal Article Proc Natl Acad Sci U S A · March 19, 1996 Heat shock proteins are proposed to limit injury resulting from diverse environmental stresses, but direct metabolic evidence for such a cytoprotective function in vertebrates has been largely limited to studies of cultured cells. We generated lines of tra ... Full text Link to item Cite

Developmental regulation of cytochrome oxidase subunit VIa isoforms in cardiac and skeletal muscle.

Journal Article Am J Physiol · February 1996 Physiological requirements for mitochondrial respiration change during fetal and postnatal development of cardiac and skeletal muscle, particularly after the abrupt transition from the hypoxic fetal environment to the oxygen-rich milieu of the neonate. Thi ... Full text Link to item Cite

Postnatal development and plasticity of specialized muscle fiber characteristics in the hindlimb.

Journal Article Dev Genet · 1996 Recent progress in defining molecular components of pathways controlling early stages of myogenesis has been substantial, but regulatory factors that govern the striking functional specialization of adult skeletal muscle fibers in vertebrate organisms have ... Full text Link to item Cite

Nuclear responses to depletion of mitochondrial DNA in human cells.

Journal Article Am J Physiol · November 1995 The derivation of human cell lines devoid of mitochondrial (mt) DNA (rho 0) provides an opportunity to study nuclear responses to a chronic impairment of mitochondrial oxidative phosphorylation. Expression of several nuclear genes is induced in human rho 0 ... Full text Link to item Cite

Effect of skeletal muscle fiber type on the pressor response evoked by static contraction in rabbits.

Journal Article J Appl Physiol (1985) · November 1995 The purpose of this study was to determine whether the reflex hemodynamic responses to static contraction of predominately glycolytic muscle are greater than the changes elicited by primarily oxidative muscle. Low-frequency electrical stimulation (continuo ... Full text Link to item Cite

Cloning and characterization of three new murine genes encoding short homologues of RNase P RNA.

Journal Article J Biol Chem · October 20, 1995 Three novel genes encoding small RNAs homologous to human and mouse RNase P RNA have been isolated from a mouse genomic library. As assessed by Northern blot analysis and nuclease protection assays, transcripts derived from one or more of these genes are e ... Full text Link to item Cite

Synergistic interactions between heterologous upstream activation elements and specific TATA sequences in a muscle-specific promoter.

Journal Article Mol Cell Biol · April 1995 Previous investigations have defined three upstream activation elements--CCAC, A/T, and TATA sequences--necessary for muscle-specific transcription of the myoglobin gene. In the present study, we demonstrate that these three sequences elements, prepared as ... Full text Link to item Cite

Boosting cardiac contractility with genes.

Journal Article N Engl J Med · March 23, 1995 Full text Link to item Cite

Neem oil inhibits two-cell embryo development and trophectoderm attachment and proliferation in vitro.

Journal Article J Assist Reprod Genet · September 1994 PURPOSE: The in vitro effect of neem oil was studied on the development of mouse two-cell embryos and trophectodermal cell attachment and proliferation. METHOD: Female mice were primed with gonadotropins for superovulation and caged with male mice. Early e ... Full text Link to item Cite

Myocyte nuclear factor, a novel winged-helix transcription factor under both developmental and neural regulation in striated myocytes.

Journal Article Mol Cell Biol · July 1994 A sequence motif (CCAC box) within an upstream enhancer region of the human myoglobin gene is essential for transcriptional activity in both cardiac and skeletal muscle. A cDNA clone, myocyte nuclear factor (MNF), was isolated from a murine expression libr ... Full text Link to item Cite

Biphasic induction of immediate early gene expression accompanies activity-dependent angiogenesis and myofiber remodeling of rabbit skeletal muscle.

Journal Article J Clin Invest · July 1994 Sustained contractile activity of skeletal muscle promotes angiogenesis, as well as transformation of contractile protein isoforms and mitochondrial proliferation within myofibers. Since the products of immediate early genes such as c-fos, c-jun, and egr-1 ... Full text Link to item Cite

Subcellular partitioning of MRP RNA assessed by ultrastructural and biochemical analysis.

Journal Article J Cell Biol · March 1994 A small RNA encoded within the nucleus is an essential subunit of a RNA processing endonuclease (RNase MRP) hypothesized to generate primers for mitochondrial DNA replication from the heavy strand origin of replication. Controversy has arisen, however, con ... Full text Link to item Cite

RNA subunit of mitochondrial RNA-processing enzyme is induced by contractile activity in striated muscle.

Journal Article Am J Physiol · December 1993 A small RNA encoded within the nucleus of yeast and mammalian cells is an essential subunit of a mitochondrial RNA-processing endonuclease (RNase MRP) that generates primers for mitochondrial DNA (mtDNA) replication. We examined expression of MRP-RNA in sp ... Full text Link to item Cite

Induction of immediate-early genes by angiotensin II and endothelin-1 in adult rat cardiomyocytes.

Journal Article J Hypertens · September 1993 OBJECTIVE: Few molecular signals for induction of myocardial hypertrophy have been identified. This study was carried out to investigate the action of angiotensin II and endothelin on the growth- and differentiation-related genes Egr-1 (early growth respon ... Full text Link to item Cite

Sequence elements required for transcriptional activity of the human myoglobin promoter in intact myocardium.

Journal Article Circ Res · August 1993 To define sequence elements required for myoglobin gene transcription in the intact heart, we examined the expression of a reporter gene under the control of a 380-bp upstream segment (-373 to +7) from the human myoglobin gene in transgenic mouse embryos a ... Full text Link to item Cite

Southwestern Internal Medicine Conference: prospects for gene therapy of ischemic heart disease.

Journal Article Am J Med Sci · August 1993 Discrete steps in the pathophysiology of ischemic heart disease present attractive potential targets for therapeutic applications of gene transfer technologies. This review develops a conceptual basis for gene therapy of ischemic heart disease and provides ... Full text Link to item Cite

Human heat shock protein 70 (hsp70) protects murine cells from injury during metabolic stress.

Journal Article J Clin Invest · July 1993 Expression of heat shock protein 70 (hsp70) is stimulated during ischemia, but its proposed cytoprotective function during metabolic stress has remained conjectural. We introduced a human hsp70 gene into mouse 10T1/2 cells and assessed the susceptibility o ... Full text Link to item Cite

Gradients of transgene expression directed by the human myoglobin promoter in the developing mouse heart.

Journal Article Proc Natl Acad Sci U S A · March 1, 1993 Prior studies using transient transfection assays in cultured avian and murine skeletal myotubes indicate that the proximal 2-kb segment of the 5' flanking region of the human myoglobin gene contains transcriptional control elements sufficient to direct mu ... Full text Link to item Cite

A 40-kilodalton protein binds specifically to an upstream sequence element essential for muscle-specific transcription of the human myoglobin promoter.

Journal Article Mol Cell Biol · November 1992 To define transcriptional control elements responsible for muscle-specific expression of the human myoglobin gene, we performed mutational analysis of upstream sequences (nucleotide positions -373 to +7 relative to the transcriptional start site) linked to ... Full text Link to item Cite

Induction of stress proteins in cultured myogenic cells. Molecular signals for the activation of heat shock transcription factor during ischemia.

Journal Article J Clin Invest · May 1992 Expression of major stress proteins is induced rapidly in ischemic tissues, a response that may protect cells from ischemic injury. We have shown previously that transcriptional induction of heat-shock protein 70 by hypoxia results from activation of DNA b ... Full text Link to item Cite

Stress proteins and cardiovascular disease.

Journal Article Mol Biol Med · April 1991 Understanding the molecular basis by which cells of the heart and blood vessels adapt to physiological stress conditions is an important goal for cardiovascular investigators. The ubiquitous heat shock response provides a model for cellular adaptations to ... Link to item Cite

Introduction of foreign genes into tissues of living mice by DNA-coated microprojectiles.

Journal Article Proc Natl Acad Sci U S A · April 1, 1991 Foreign genes were expressed in liver and skin cells of live mice by using a new apparatus to accelerate DNA-coated microprojectiles into tissues. After introduction of a plasmid in which the firefly luciferase gene was controlled by the human beta-actin p ... Full text Link to item Cite

Mitochondrial biogenesis in striated muscles: rapid induction of citrate synthase mRNA by nerve stimulation.

Journal Article Am J Physiol · February 1991 Tonic contractile activity induces mitochondrial biogenesis in mammalian skeletal muscles, necessitating regulation of both nuclear and mitochondrial genes encoding mitochondrial proteins. In this study we compared the time course of induction of citrate s ... Full text Link to item Cite

Molecular biology in cardiology: recent developments and opportunities for clinical applications.

Journal Article Am J Med Sci · November 1990 The revolution in molecular biology that has taken place in the last decade has provided powerful research methods that are changing our understanding of cardiovascular physiology and disease. This editorial commentary will highlight several areas of curre ... Full text Link to item Cite

Mitochondrial DNA structure and expression in specialized subtypes of mammalian striated muscle.

Journal Article Mol Cell Biol · November 1990 Mitochondrial DNA (mt DNA) in cells of vertebrate organisms can assume an unusual triplex DNA structure known as the displacement loop (D loop). This triplex DNA structure forms when a partially replicated heavy strand of mtDNA (7S mtDNA) remains annealed ... Full text Link to item Cite

Activation of the heat shock transcription factor by hypoxia in mammalian cells.

Journal Article Proc Natl Acad Sci U S A · August 1990 Members of the stress protein family such as HSP70 are induced in ischemic tissues and may contribute to the ability of cells to survive episodes of transient circulatory insufficiency. However, the biochemical events that lead to this induction, and their ... Full text Link to item Cite

Increased expression of fibroblast growth factors in a rabbit skeletal muscle model of exercise conditioning.

Journal Article J Clin Invest · June 1990 Increased tonic contractile activity from exercise or electrical stimulation induces a variety of changes in skeletal muscle, including vascular growth, myoblast proliferation, and fast to slow fiber type conversion. Little is known about the cellular cont ... Full text Link to item Cite

Functional heterogeneity of mammalian TATA-box sequences revealed by interaction with a cell-specific enhancer.

Journal Article Nature · March 15, 1990 A regulatory element upstream of the human myoglobin gene functions as a muscle-specific enhancer (MSE) in conjunction with core promoter elements of the myoglobin gene, but not in combination with the simian virus 40 (SV40) early promoter. These two promo ... Full text Link to item Cite

Cardiovascular and behavioral effects of aerobic exercise training in healthy older men and women.

Journal Article J Gerontol · September 1989 The cardiovascular and behavioral adaptations associated with a 4-month program of aerobic exercise training were examined in 101 older men and women (mean age = 67 years). Subjects were randomly assigned to an Aerobic Exercise group, a Yoga and Flexibilit ... Full text Link to item Cite

Identification of a muscle-specific enhancer within the 5'-flanking region of the human myoglobin gene.

Journal Article J Biol Chem · August 15, 1989 A 2-kilobase fragment from the 5'-flanking region of the human myoglobin gene extending from -2038 to +7 relative to the cap site regulates expression of a heterologous reporter gene in a cell-specific and developmentally regulated manner. Functional analy ... Link to item Cite

Interactions between sustained contractile activity and beta-adrenergic receptors in regulation of gene expression in skeletal muscles.

Journal Article Am J Physiol · March 1989 Continuous electrical stimulation for 10-21 days of the motor nerve innervating the anterior compartment muscles of adult rabbits increased both the density of beta-adrenergic receptors (beta-AR) and tissue concentrations of adenosine 3',5'-cyclic monophos ... Full text Link to item Cite

Coordinate changes in fast thin filament and Z-line protein expression in the early response to chronic stimulation.

Journal Article J Biol Chem · October 5, 1988 The early response to chronic low frequency stimulation is characterized by coordinate changes in fast thin filament and Z-line protein expression prior to the expression of slow contractile proteins. Within the first 3 weeks of intervention there is 1) a ... Link to item Cite

Activity-induced adaptations in skeletal muscles of iron-deficient rabbits.

Journal Article J Appl Physiol (1985) · August 1988 The purpose of this study was to determine whether severe iron deficiency alters the adaptive response of skeletal muscle fibers to a sustained increase in tonic contractile activity. Seven weanling rabbits consumed a low iron diet and underwent phlebotomy ... Full text Link to item Cite

Comparison of high- and low-intensity exercise training early after acute myocardial infarction.

Journal Article Am J Cardiol · January 1, 1988 The effects of the intensity of exercise training on cardiorespiratory variables were investigated in a consecutive series of men with recent (median 8 weeks) acute myocardial infarction. Forty-five patients were randomly assigned either to a high- (65 to ... Full text Link to item Cite

Effects of inhibition of mitochondrial protein synthesis in skeletal muscle.

Journal Article Am J Physiol · December 1987 To evaluate the participation of proteins derived from mitochondrial genes in the adaptive response of skeletal muscle to increased contractile activity, we administered chloramphenicol (CAP; 200-1,000 mg.kg-1.day-1), an inhibitor of translation from mitoc ... Full text Link to item Cite

Exercise-induced functional desensitization of canine cardiac beta-adrenergic receptors.

Journal Article J Appl Physiol (1985) · April 1987 To test the hypothesis that the high levels of endogenous catecholamines associated with strenuous exercise produce functional desensitization of cardiac beta-adrenergic receptors, we measured the bolus chronotropic dose of isoproterenol necessary to produ ... Full text Link to item Cite

Pretranslational regulation of myoglobin gene expression.

Journal Article Am J Physiol · April 1987 We have used blot hybridization techniques and a specific anti-sense RNA probe to determine whether variation in myoglobin gene expression among mammalian striated muscles is attributable to pretranslational regulatory events. We observed that myoglobin mR ... Full text Link to item Cite

Adaptation of skeletal muscle to increased contractile activity. Expression nuclear genes encoding mitochondrial proteins.

Journal Article J Biol Chem · February 25, 1987 An increase in mitochondrial biogenesis in mammalian cells requires a coordinated increase in the expression of a number of nuclear genes that encode mitochondrial proteins. To examine the regulatory mechanisms involved, we used specific anti-sense RNA pro ... Link to item Cite

Beta adrenergic blockade with propranolol and atenolol in the exercising dog: evidence for beta 2 adrenoceptors in the sinoatrial node.

Journal Article Cardiovasc Res · February 1987 To test the hypothesis that beta 2 adrenergic receptors mediate the chronotropic more than the inotropic response to endogenous catecholamines the effects on the haemodynamic responses to exercise in dogs of the beta 1 specific antagonist atenolol were com ... Full text Link to item Cite

Mitochondrial gene expression in mammalian striated muscle. Evidence that variation in gene dosage is the major regulatory event.

Journal Article J Biol Chem · September 15, 1986 The oxidative capacity of mammalian striated muscles can vary markedly over a nearly 10-fold range, reflecting major differences in the expression of genes that encode enzymes of oxidative metabolism, including genes located exclusively within mitochondria ... Link to item Cite

Age-dependent changes in expression of alpha 1-adrenergic receptors in rat myocardium.

Journal Article Biochem Biophys Res Commun · July 16, 1986 The expression of alpha 1-adrenergic receptors within ventricular myocardium of rats ranging in age from 21 days of fetal life to 24 months after birth was measured from [125I] 2-(beta hydroxy phenyl) ethylaminomethyl tetralone binding isotherms. No differ ... Full text Link to item Cite

Physiologic basis for the age-related decline in aerobic work capacity.

Journal Article Am J Cardiol · June 1, 1986 To determine the physiologic mechanisms of the decline in aerobic work performance with age, a cross-sectional study was performed. Twenty-four sedentary male volunteers, aged 20 to 50 years, underwent right-sided cardiac catheterization, arterial cannulat ... Full text Link to item Cite

Regulation of stroke volume during submaximal and maximal upright exercise in normal man.

Journal Article Circ Res · February 1986 To characterize the hemodynamic factors that regulate stroke volume during upright exercise in normal man, 24 asymptomatic male volunteers were evaluated by simultaneous right heart catheterization, radionuclide angiography, and expired gas analysis during ... Full text Link to item Cite

Regulation of nuclear and mitochondrial gene expression by contractile activity in skeletal muscle.

Journal Article J Biol Chem · January 5, 1986 Increased contractile activity of skeletal muscle augments the volume fraction and enzymatic capacity of mitochondria and suppresses the enzymatic capacity of several cytoplasmic enzymes of glycolysis. To examine the biochemical mechanisms underlying these ... Link to item Cite

Role of receptor mechanisms in the adaptive response to habitual exercise.

Journal Article Am J Cardiol · April 26, 1985 Many of the physiologic adaptations that occur in response to habitual exercise are associated with changes in neuroendocrine control of specific cell and tissue functions. Because all of the hormones and neurotransmitters important to exercise physiology ... Full text Link to item Cite

Beta 1-selective and non-selective beta-adrenoceptor blockade, anaerobic threshold and respiratory gas exchange during exercise.

Journal Article Br J Clin Pharmacol · January 1985 The effect of oral doses of the beta 1-selective adrenoceptor antagonist atenolol (50 mg), the non-selective antagonist propranolol (40 mg) and placebo was investigated during exercise in a crossover comparison in six healthy but untrained subjects. Descri ... Full text Link to item Cite

Effects of physical conditioning on left ventricular ejection fraction in patients with coronary artery disease.

Journal Article Circulation · July 1984 To address the hypothesis that physical conditioning may improve left ventricular function in patients with coronary artery disease, we performed first-pass radionuclide ventriculography in 53 patients at rest and during upright bicycle exercise before and ... Full text Link to item Cite

Effects of beta 1-selective and nonselective beta-adrenoceptor blockade during exercise conditioning in healthy adults.

Journal Article Am J Cardiol · June 1, 1984 The interaction of beta 1-selective (cardioselective) and nonselective beta-adrenoceptor blockade with exercise conditioning was investigated in 30 healthy adult persons. A double-blind protocol was used and the effects of atenolol (100 mg/day), propranolo ... Full text Link to item Cite

Feasibility and benefits of exercise training in patients on maintenance dialysis.

Journal Article Kidney Int · June 1984 Fourteen of 174 patients receiving maintenance dialysis volunteered to participate in a 12-week exercise conditioning program. Seven patients attended more than 50% (range, 55 to 75%) of the sessions held three times each week. These seven patients achieve ... Full text Link to item Cite

Effects of endurance training on cholinergic and adrenergic receptors of rat heart.

Journal Article J Mol Cell Cardiol · May 1984 To test the hypothesis that alterations in adrenergic or cholinergic receptors occur in response to physical training, and that changes in receptor properties could be mechanistically important in producting the altered cardiovascular physiology of the tra ... Full text Link to item Cite

Hemodynamic and metabolic responses to exercise after adrenoceptor blockade in humans.

Journal Article J Appl Physiol Respir Environ Exerc Physiol · March 1984 The effects of acute alpha 1-adrenoceptor blockade with prazosin, beta 1-adrenoceptor blockade with atenolol, and nonselective beta-adrenoceptor blockade with propranolol were compared in a placebo-controlled crossover study of the hemodynamic and metaboli ... Full text Link to item Cite

Hemodynamic and metabolic responses to exercise after alpha 1-, beta 1-, and nonselective beta-adrenoceptor blockade in man.

Journal Article Am J Med · February 27, 1984 The effects of acute alpha 1-adrenoceptor blockade with prazosin, beta 1-adrenoceptor blockade with atenolol, and nonselective beta-adrenoceptor blockade with propranolol were compared in a placebo-controlled crossover study. The study involved measurement ... Full text Link to item Cite

Skeletal muscle beta-adrenergic receptors: variations due to fiber type and training.

Journal Article Am J Physiol · February 1984 To determine the relationship between oxidative capacity and characteristics of beta-adrenergic receptors (beta AR) in skeletal muscle, selected biochemical variables were quantitated in particulate preparations from soleus and gastrocnemius muscle from ra ... Full text Link to item Cite

Effects of experimental diabetes on adrenergic and cholinergic receptors of rat myocardium.

Journal Article Diabetes · October 1983 To more fully characterize the alterations in myocardial adrenergic and cholinergic receptors induced by the diabetic state, we investigated the binding characteristics of (--) [3H] dihydroalprenolol to beta adrenergic receptors (bAR), [3H] prazosin to alp ... Full text Link to item Cite

Differentiation of hemodynamic, humoral and metabolic responses to beta 1- and beta 2-adrenergic stimulation in man using atenolol and propranolol.

Journal Article Circulation · May 1983 The respective contributions of beta-adrenoceptor subtypes to the hemodynamic, humoral and metabolic consequences of adrenergic stimulation during graded exercise in man were investigated using nonselective beta-adrenoceptor blockade with propranolol and b ... Full text Link to item Cite

The basis for the increase in factor VIII procoagulant activity during exercise.

Journal Article Thromb Haemost · February 28, 1983 We studied the effect of acute exercise on the ability of thrombin to activate plasma factor VIII (FVIII) activity in 20 healthy males. The subject showed an average exercise-related increase in FVIII activity of 54.5 +/- 8.2% over pre-exercise FVIII activ ... Link to item Cite

Psychological changes accompany aerobic exercise in healthy middle-aged adults.

Journal Article Psychosom Med · December 1982 An attempt was made to assess the effects of aerobic exercise on the psychological functioning of a nonclinical sample of healthy middle-aged adults. Sixteen subjects participated in a 10-week program of regular walking-jogging, while a matched control gro ... Full text Link to item Cite

Physiological and psychological variables predict compliance to prescribed exercise therapy in patients recovering from myocardial infarction.

Journal Article Psychosom Med · December 1982 Previous research has documented high rates of noncompliance to prescribed medical therapy in patients recovering from myocardial infarction (MI). This study was undertaken to determine if patients who subsequently drop out of a structured cardiac rehabili ... Full text Link to item Cite

Enhanced receptor-cyclase coupling and augmented catecholamine-stimulated lipolysis in exercising rats.

Journal Article Am J Physiol · November 1982 To test the hypothesis that alterations of adipocyte beta-adrenergic receptors provide a molecular mechanism for enhanced catecholamine-stimulated lipolysis in physically trained animals, we studied adipocytes derived from rats subjected to 14 wk of swimmi ... Full text Link to item Cite

Effects of exercise training on ventricular function in patients with recent myocardial infarction.

Journal Article Circulation · July 1982 We evaluated the effects of 6 months of exercise training (bicycle ergometry, walking and jogging) on exercise performance and ventricular function in patients with recent myocardial infarction. Fifteen patients were selected on the basis of myocardial inf ... Full text Link to item Cite

Exercise responses before and after physical conditioning in patients with severely depressed left ventricular function.

Journal Article Am J Cardiol · February 1, 1982 The ability of patients with severely impaired left ventricle function to perform short-term exercise and to participate in a cardiac rehabilitation program and attain physical training effects was evaluated. Treadmill exercise tests were performed before ... Full text Link to item Cite

Cholesterol controversy--where do we go from here? 'Toward healthful diets' reevaluated.

Journal Article Cardiology · 1982 The document, entitled 'Toward Healthful Diets' that was developed by the Food and Nutrition Board of the National Academy of Sciences last year, has again stirred major controversy among the general public and in the medical community regarding the diet-h ... Full text Link to item Cite

Autonomic mechanisms of training bradycardia: beta-adrenergic receptors in humans.

Journal Article J Appl Physiol Respir Environ Exerc Physiol · November 1981 To address the autonomic mechanisms underlying the bradycardia of physical training in human subjects, we performed a cross-sectional study comparing the heart-rate responses to graded doses of isoproterenol in 7 elite marathon runners and 7 age-matched co ... Full text Link to item Cite

Medical aspects of competitive distance running: guidelines for community physicians.

Journal Article Postgrad Med · July 1981 While the incidence of major medical emergencies during competitive distance running is low, the large and growing number of persons involved, including the elderly, mandates serious attention by the medical community to provision of adequate prevention an ... Full text Link to item Cite

Selectivity of dobutamine for adrenergic receptor subtypes: in vitro analysis by radioligand binding.

Journal Article J Clin Invest · June 1981 The cardiovascular responses elicited by dobutamine are distinctly different from those produced by other adrenergic or dopaminergic agonists. To test the hypothesis that dobutamine could have differential affinities for adrenergic receptor subtypes, and t ... Full text Link to item Cite

Paroxysmal hypotension associated with sympathetic withdrawal. A new disorder of autonomic vasomotor regulation.

Journal Article Circulation · October 1980 We evaluated a patient who had transient episodes of hypotension with clinical and laboratory features apparently distinct from previously recognized disorders of vasomotor regulation. In between his abrupt attacks of hypotension, the patient is asymptomat ... Full text Link to item Cite

Physical conditioning augments the fibrinolytic response to venous occlusion in healthy adults.

Journal Article N Engl J Med · May 1, 1980 The effects of a 10-week physical-conditioning program on fibrinolytic activity at rest and after stimulation by venous occlusion were studied in 69 healthy adults 25 to 69 years old. Physical conditioning was documented by treadmill performance, and fibri ... Full text Link to item Cite

Physical conditioning and membrane receptors for cardioregulatory hormones.

Journal Article Cardiovasc Res · March 1980 To seek possible mechanisms for the relative bradycardia induced by physical conditioning we studied the effects of an eight-week swimming programme upon cardiac beta-adrenergic and muscarinic-cholinergic receptors in rats. A training effect was documented ... Full text Link to item Cite

Effects of exercise on the Type A (coronary prone) behavior pattern.

Journal Article Psychosom Med · March 1980 This study presents the initial findings of an attempt to reduce the risk of coronary heart disease (CHD) in a group of health, middle-aged adults by participation in a ten-week, supervised exercise program. Forty-six subjects were classified as Type A or ... Full text Link to item Cite

Left bundle branch block: angiographic segmental wall motion abnormalities.

Journal Article Am J Cardiol · November 1979 Ventricular wall motion as studied with contrast ventriculography has been judged normal in the few previously reported cases of patients with left bundle branch block who have neither coronary artery disease nor diffuse cardiomyopathy. However, recent ech ... Full text Link to item Cite

Cholesterol metabolism in non-obese women--Failure of physical conditioning to alter levels of high density lipoprotein cholesterol.

Journal Article Atherosclerosis · October 1979 The effects of a 6-week program of vigorous exercise were studied in 14 non-obese females aged 22--26. Preceding and following a regimen consisting of 30--45 min of jogging 5 days per week, treadmill performance, body weight, total plasma cholesterol, and ... Full text Link to item Cite

Beta-Adrenergic receptors of human lymphocytes are unaltered by hyperthyroidism.

Journal Article J Clin Endocrinol Metab · March 1979 Lymphocytes from 12 patients with untreated hyperthyroidism were compared to lymphocytes from age- and sex-matched euthyroid control subjects to test the hypothesis that alterations in beta-adrenergic response mechanisms occur in human hyperthyroidism. The ... Full text Link to item Cite

Alpha-adrenergic receptors in rat myocardium. Identification by binding of [3H]dihydroergocryptine.

Journal Article Circ Res · November 1978 [3H]Dihydroergocryptine ([3H]DHE) binds to sites in membranes derived from rat myocardium that have the characteristics expected of alpha-adrenergic receptors. The binding is saturable with 41 fmol [3H]DHE bound per mg of protein and of high affinity with ... Full text Link to item Cite