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Fadia Haddad

Publications and source records attributed to Fadia Haddad.

At least 19 recordsLinked to original sources
PubMed2026

Endurance training attenuates acute exercise-induced monocyte transcriptomic responses in adolescents: sex-specific molecular adaptations.

Circulating monocytes contribute to atherogenesis and vascular dysfunction. Although clinical cardiovascular disease presents in adulthood, its biological origins often begin in youth and differ substantially between females and males. Twelve males and nine females (13-17 yr) completed an acute exercise protocol consisting of 10, 2-min cycling bouts at 70% of maximal work rate interspersed with 1-min rest intervals, performed before and after an 8-wk supervised endurance training intervention with brief supplementary strength work (60 min/session, 3 sessions/wk). Blood was collected before and immediately after each exercise challenge. Peripheral blood monocytes were isolated, and whole transcriptome RNA sequencing (RNA-seq) was performed. Before training, acute exercise induced a markedly greater monocyte transcriptomic response in females compared with males [5,135 vs. 567 differentially expressed transcripts, false discovery rate (FDR) < 0.1]. Pathway analyses identified vascular function-related pathways in males, whereas females showed enrichment of pathways related to adipose tissue cross talk and oxidative metabolism. Following training, the acute transcriptomic response was markedly attenuated in both sexes (165 transcripts in males and 94 in females, FDR < 0.1), representing an &#x223c;98% reduction in females and a &#x223c;70% reduction in males relative to pre-training responses. These findings reveal sex-specific monocyte responses to acute exercise in youth and suggest that endurance exercise alters immune transcriptional responsiveness in pathways relevant to vascular and cardiovascular health.NEW & NOTEWORTHY Acute exercise induced a markedly greater monocyte transcriptomic response in female adolescents than in males. Females showed activation of pathways related to adipose tissue signaling and oxidative metabolism, whereas males exhibited vascular-function pathways. Following exercise training, the monocyte transcriptomic response to acute exercise was substantially attenuated in both sexes. These findings identify sex-specific immune transcriptional responses to exercise during adolescence with potential implications for cardiovascular health.

Humans↗
PubMed2007

Molecular and cellular defects of skeletal muscle in an animal model of acute quadriplegic myopathy.

Muscle denervation and concomitant high-dose dexamethasone treatment in rodents produces characteristic pathologic features of severe muscle atrophy and selective myosin heavy filament (MyHC) depletion, identical to those seen in acute quadriplegic myopathy (AQM), also known as critical illness myopathy. We tested the hypothesis that defective pre-translational processes contribute to the atrophy and selective MyHC depletion in this model. We examined the effects of combined glucocorticoid-denervation treatment on MyHC and actin mRNA populations; we also studied mRNA expression of the myogenic regulatory factors (MRFs), primary transcription factors for MyHC. Adult female rats were subjected to proximal sciatic denervation followed by high-dose dexamethasone (DD) treatment (5 mg/kg body weight daily) for 7 days. Disease controls included rats treated with denervation alone (DN) or dexamethasone alone (DX). At 1 week the plantaris atrophied by approximately 42% in DD muscles. DD treatment resulted in selective MyHC protein depletion; actin protein concentration was not significantly changed. Despite an increase in total RNA concentration in DN and DD muscles, MyHC and actin mRNA concentrations were significantly decreased in these muscles. MyHC mRNA showed a significantly more extensive depletion relative to actin mRNA in DD muscles. Glucocorticoid treatment did not influence a denervation-induced increase in the mRNA expression of the MRFs. We conclude that a deleterious interaction between glucocorticoid and denervation treatments in skeletal muscle is responsible for pre-translational defects that reduce actin and MyHC mRNA substrates in a disproportionate fashion. The resultant selective MyHC depletion contributes to the severe muscle atrophy.

Actins↗
PubMed2006

Dynamics of myosin heavy chain gene regulation in slow skeletal muscle: role of natural antisense RNA.

The evolutionarily conserved order of the skeletal muscle myosin heavy chain (MHC) genes and their close tandem proximity on the same chromosome are intriguing and may be important for their coordinated regulation. We investigated type II MHC gene regulation in slow-type muscle fibers undergoing a slow to fast MHC transformation in response to inactivity, 7 days after spinal cord isolation (SI) in rats. We examined the transcriptional products of both the sense and antisense strands across the IIa-IIx-IIb MHC gene locus. A strand-specific reverse transcription (RT)-PCR approach was utilized to study the expression of the mRNA, the primary transcript (pre-mRNA), the antisense RNA overlapping the MHC genes, and both the intergenic sense and antisense RNAs. Results showed that the mRNA and pre-mRNA of each MHC had a similar response to SI, suggesting regulation of these genes at the transcriptional level. In addition, we detected previously unknown antisense strand transcription that produced natural antisense transcripts (NATs). RT-PCR mapping of the RNA products revealed that the antisense activity resulted in the formation of three major products: aII, xII, and bII NATs (antisense products of the IIa, IIx, and IIb genes, respectively). The aII NAT begins in the IIa-IIx intergenic region in close proximity to the IIx promoter, extends across the 27-kb IIa MHC gene, and continues to the IIa MHC gene promoter. The expression of the aII NAT was significantly up-regulated in muscles after SI, was negatively correlated with IIa MHC gene expression, and was positively correlated with IIx MHC gene expression. The exact role of the aII NAT is not clear; however, it is consistent with the inhibition of IIa MHC gene transcription. In conclusion, NATs may mediate cross-talk between adjacent genes, which may be essential to the coordinated regulation of the skeletal muscle MHC genes during dynamic phenotype shifts.

Animals↗
PubMed2006

Staged anesthesia for combined carotid and coronary artery revascularization: a different approach.

OBJECTIVE: Combined coronary artery bypass graft (CABG) surgery and carotid endarterectomy (CEA) are performed in an attempt to reduce the risk of postoperative stroke after CABG surgery in patients with significant or symptomatic carotid artery stenosis. The choice between regional and general anesthesia for CEA is still under debate. Regional anesthesia offers an excellent monitoring technique of the neurologic status of the awake patient during carotid clamping. In an attempt to improve monitoring of the neurologic status and avoid the use of temporary shunting in patients undergoing the combined procedure, a different approach is described combining regional anesthesia for CEA followed immediately by general anesthesia for CABG surgery. DESIGN: Prospective nonrandomized case series. SETTING: University hospital. PARTICIPANTS: Twenty patients scheduled for combined CEA and CABG surgery underwent a "staged" anesthetic approach from January to December 2004. INTERVENTIONS: Pulmonary, femoral artery, and urinary catheters were inserted under local anesthesia. A deep cervical plexus block was then performed and supplemented by a superficial cervical plexus block. The patient was draped for standard combined CEA and CABG surgery. CEA was then performed using standard techniques. Without altering the surgical field, general anesthesia was given and endotracheal intubation performed following the successful CEA. Coronary revascularization was then completed. MEASUREMENTS AND MAIN RESULTS: CEA and CABG surgery were completed successfully in all patients. There was no need for conversion from local to general anesthesia. Endotracheal intubation was easily performed in all patients. There was no hospital mortality in this series. No neurologic events were observed during the CEA. A reversible ischemic stroke, ipsilateral to the CEA, occurred postoperatively on awakening from CABG surgery in 1 patient. CONCLUSIONS: This staged anesthetic approach for combined CABG and CEA surgery is an alternative in this complex subset of patients.

Aged↗
PubMed2006

Expression of insulin-like growth factor I, insulin-like growth factor binding proteins, and collagen mRNA in mechanically loaded plantaris tendon.

Insulin-like growth factor I (IGF-I) is known to exert an anabolic effect on tendon fibroblast production of collagen. IGF-I's regulation is complex and involves six different IGF binding proteins (IGFBPs). Of these, IGFBP-4 and -5 could potentially influence the effect of IGF-I in the tendon because they both are produced in fibroblast; however, the response of IGFBP-4 and -5 to mechanical loading and their role in IGF-I regulation in tendinous tissue are unknown. A splice variant of IGF-I, mechano-growth factor (MGF) is upregulated and known to be important for adaptation in loaded muscle. However, it is not known whether MGF is expressed and upregulated in mechanically loaded tendon. This study examined the effect of mechanical load on tendon collagen mRNA in relation to changes in the IGF-I systems mRNA expression. Data were collected at 2, 4, 8 and 16 days after surgical removal of synergistic muscle to the plantaris muscle of the rat, thus increasing the load to plantaris muscle and tendon. Nearly a doubling of the tendon mass was observed after 16 days of loading. A rapid rise in tendon procollagen III mRNA was seen after 2 days whereas the increase in procollagen I mRNA was significant from day 8. MGF was expressed and upregulated in loaded tendon tissue with a faster response than IGF-I, which was increased from day 8. Finally, IGFBP-4 mRNA was increased with a time pattern similar to procollagen III, whereas IGFBP-5 decreased at day 8. In conclusion, loading of tendon tissue results in an upregulation of IGF-I, IGFBP-4, and procollagen and is associated with an increase in tendon mass. Also, MGF is expressed with an early upregulation in loaded tendon tissue. We suggest that the IGF-I system could be involved in collagen synthesis in tendon in response to mechanical loading.

Animals↗
PubMed2005

Aging-sensitive cellular and molecular mechanisms associated with skeletal muscle hypertrophy.

Sarcopenia is an age-related loss of muscle mass and strength. The aged can increase various measures of muscle size and strength in response to resistance exercise (RE), but this may not normalize specific tension. In rats, aging reduces the hypertrophy response and impairs regeneration. In this study, we measured cellular and molecular markers, indicative of muscle hypertrophy, that also respond to acute increases in loading. Comparing 6- and 30-mo-old rats, the aims were to 1) determine whether these markers are altered with age and 2) identify age-sensitive responses to acute RE. The muscles of old rats exhibited sarcopenia involving a deficit in contractile proteins and decreased force generation. The RNA-to-protein ratio was higher in the old muscles, suggesting a decrease in translational efficiency. There was evidence of reduced signaling via components downstream from the insulin/insulin-like growth factor (IGF)-I receptors in old muscles. The mRNA levels of myostatin and suppressor of cytokine signaling 2, negative regulators of muscle mass, were lower in old muscles but did not decrease following RE. RE induced increases in the mRNAs for IGF-I, mechano-growth factor, cyclin D1, and suppressor of cytokine signaling 3 were similar in old and young muscles. RE induced phosphorylation of the IGF-I receptor, and Akt increased in young but not old muscles, whereas that of S6K1 was similar for both. The results of this study indicate that a number of components of intracellular signaling pathways are sensitive to age. As a result, key anticatabolic responses appear to be refractory to the stimuli provided by RE.

Aging↗
PubMed2005

Intraoperative myocardial ischemia in peripheral vascular surgery: general anesthesia vs combined sciatic and femoral nerve blocks.

STUDY OBJECTIVE: The aim of this study was to compare the frequency of intraoperative myocardial ischemia in lower extremity vascular surgery with general anesthesia vs regional anesthesia via combined sciatic and femoral nerve blocks. DESIGN: This is a prospective, randomized study. SETTING: This study was set at an academic medical center. PATIENTS: The study included 50 patients scheduled for elective lower extremity vascular surgery. INTERVENTIONS: Patients in group 1 received balanced general anesthesia, whereas patients in group 2 received combined sciatic and femoral nerve blocks with 40 mL of 0.375% bupivacaine. Monitoring included a radial artery catheter and multilead, dual-channel electrocardiogram with computerized ST-segment analysis. Blood pressure and heart rate variations were maintained within 10% of preoperative values by adjusting anesthetic depth, fluid replacement, and vasoactive drug dosages. MEASUREMENTS AND MAIN RESULTS: An ST-segment depression of at least 1 mm or elevation of at least 2 mm lasting for more than 1 minute was considered a significant episode of myocardial ischemia. Intraoperative hemodynamic data and the frequency of significant ST-segment change episodes were recorded. The number of patients with ischemic episodes and the total number of these episodes were lower in group 2 than in group 1 (1 patient vs 7 patients, P = 0.02; and 2 vs 14 episodes, P = 0.04). No significant difference was found between groups 1 and 2 regarding systolic or diastolic arterial pressures, or heart rate. CONCLUSION: Compared with general anesthesia, combined sciatic and femoral nerve blocks reduce the frequency of intraoperative myocardial ischemia in patients undergoing lower extremity vascular surgery.

Aged↗
PubMed2005

Voluntary exercise during chronic renal failure in rats.

PURPOSE: Chronic renal failure (CRF) patients often experience a significant degradation in quality of life that is associated with decreased physical fitness. Previous animal studies have used forced running or swimming as modalities to investigate the interactions between exercise and CRF. These modalities generally include stress responses unrelated to the exercise itself. The purpose of the current work was to determine whether, and to what extent, rats experiencing the onset of CRF would participate in voluntary wheel running exercise. An additional objective was to examine physiological parameters related to skeletal muscle and cardiovascular adaptation in the context of CRF and exercise. METHODS: Groups of rats were assigned to sham-operated or 5/6 nephrectomy groups, and further divided into running or nonrunning subgroups. Blood, heart, and muscle tissues were collected 30 d after the exercise groups were returned to running wheel-equipped cages. RESULTS: The results demonstrated that rats experiencing the early stages of CRF will voluntarily exercise to the same extent as sham-operated animals (e.g., sham, 7.2+/-0.8 vs CRF, 6.8+/-0.7 km.d). CRF resulted in increased systolic blood pressure that was not normalized by exercise. CRF induced a decrease in hemoglobin concentration that was prevented by exercise. Voluntary running resulted in an apparently nonpathological left ventricular hypertrophy in both the sham-operated and CRF rats. In locomotor skeletal muscles, CRF resulted in a 31% decrease in citrate synthase activity that was completely blunted by voluntary running activity. CONCLUSION: Rats experiencing the onset of CRF will run voluntarily. This exercise appears to provide some potentially palliative effects on the skeletal muscle and cardiovascular responses to CRF.

Animals↗
PubMed2004

Effect of unloading on type I myosin heavy chain gene regulation in rat soleus muscle.

Slow-twitch soleus, a weight-bearing hindlimb muscle, predominantly expresses the type I myosin heavy chain (MHC) isoform. However, under unloading conditions, a transition in MHC expression occurs from slow type I toward the fast-type isoforms. Transcriptional processes are believed to be involved in this adaptation. To test the hypothesis that the downregulation of MHC1 in soleus muscle following unloading is controlled through cis element(s) in the proximal region of the promoter, the MHC1 promoter was injected into soleus muscles of control rats and those subjected to 7 days of hindlimb suspension. Mutation analyses of six putative regulatory elements within the -408-bp region demonstrated that three elements, an A/T-rich, the proximal muscle-type CAT (betae3), and an E-box (-63 bp), play an important role in the basal level of MHC1 gene activity in the control soleus and function as unloading-responsive elements. Gel mobility shift assays revealed a diminished level of complex formation of the betae3 and E-box probes with nuclear extract from hindlimb suspension soleus compared with control soleus. Supershift assays indicated that transcriptional enhancer factor 1 and myogenin factors bind the betae3 and E-box elements, respectively, in the control soleus. Western blots showed that the relative concentrations of the transcriptional enhancer factor 1 and myogenin factors were significantly attenuated in the unloaded soleus compared with the control muscle. We conclude that the downregulation of MHC1 in response to unloading is due, in part, to a significant decrease in the concentration of these transcription factors available for binding the positive regulatory elements.

Adaptation, Physiological↗
PubMed2004

Time course of molecular responses of human skeletal muscle to acute bouts of resistance exercise.

Resistance exercise (RE) training, designed to induce hypertrophy, strives for optimal activation of anabolic and myogenic mechanisms to increase myofiber size. Clearly, activation of these mechanisms must precede skeletal muscle growth. Most mechanistic studies of RE have involved analysis of outcome variables after many training sessions. This study measured molecular level responses to RE on a scale of hours to establish a time course for the activation of myogenic mechanisms. Muscle biopsy samples were collected from nine subjects before and after acute bouts of RE. The response to a single bout was assessed at 12 and 24 h postexercise. Further samples were obtained 24 and 72 h after a second exercise bout. RE was induced by neuromuscular electrical stimulation to generate maximal isometric contractions in the muscle of interest. A single RE bout resulted in increased levels of mRNA for IGF binding protein-4 (84%), MyoD (83%), myogenin (approximately 3-fold), cyclin D1 (50%), and p21-Waf1 (16-fold), and a transient decrease in IGF-I mRNA (46%). A temporally conserved, significant correlation between myogenin and p21 mRNA was observed (r = 0.70, P < or = 0.02). The mRNAs for mechano-growth factor, IGF binding protein-5, and the IGF-I receptor were unchanged by RE. Total skeletal muscle RNA was increased 72 h after the second serial bout of RE. These results indicate that molecular adaptations of skeletal muscle to loading respond in a very short time. This approach should provide insights on the mechanisms that modulate adaptation to RE and may be useful in evaluating RE training protocol variables with high temporal resolution.

Adaptation, Physiological↗
PubMed2004

Cloning and sequencing of myosin heavy chain isoform cDNAs in golden-mantled ground squirrels: effects of hibernation on mRNA expression.

The golden-mantled ground squirrel is a small rodent hibernator that demonstrates unusual myosin heavy chain (MHC) isoform plasticity during several months of torpor, punctuated by bouts of rewarming and shivering thermogenesis. We measured MHC mRNA levels to determine whether pretranslational control mechanisms were responsible for differences in MHC2x protein expression, as we previously observed between active and hibernating ground squirrels. We first cloned cDNA using the 3' rapid amplification of cDNA ends (3' RACE) technique and identified three sequences corresponding to MHC1, MHC2x, and MHC2b. A DNA control fragment was developed to be used in conjunction with a coupled RT-PCR reaction to simultaneously measure MHC mRNA levels for each isoform in the skeletal muscle of ground squirrels. MHC mRNA and protein expression were strongly correlated, and type IIx and IIb mRNA levels were significantly different between active and hibernating ground squirrels. Pretranslational control of MHC protein is apparently an important process during hibernation, although the exact stimulus is not known. The techniques presented can be used to obtain MHC cDNA sequences and to measure mRNA expression in many vertebrate groups.

Animals↗
PubMed2004

Effect of cyclosporin A treatment on the in vivo regulation of type I MHC gene expression.

Rat soleus muscle consists predominantly of slow type I fibers. We have shown previously through deletion analysis that the highest level of reporter activity that we measure when injecting type I myosin heavy chain (MHC) promoter (MHC(1))-linked luciferase plasmid into soleus muscles depends on the presence of a 550-bp upstream enhancer (3,450-2,900) region of the promoter. Because the calcineurin-nuclear factor of activated T cells (NFAT) pathway has been implicated in the regulation of the slow muscle gene program, particularly the MHC(1) isoform, and the MHC(1) promoter contains several putative NFAT sites, we examined via deletion and mutation analyses whether this pathway is involved in the regulation of promoter activity in soleus. Nine days of treatment with the calcineurin inhibitor cyclosporin A (CsA) caused a significant decrease in activity of the -3,500- and -3,450-bp promoters compared with vehicle-treated rats. Truncation of the promoter to -2,900 bp or smaller reduced the activity and also eliminated the CsA responsiveness, thus implying that the enhancer region is required for CsA responsiveness. Surprisingly, mutating the two NFAT elements within the enhancer region had no obvious effect on promoter activity. CsA treatment resulted in an increase in the mRNA levels of fast-type IIa and IIx MHC isoforms, but RT-PCR analysis of MHC(1) pre-mRNA and mature mRNA expression in soleus muscles revealed no differences between vehicle- and CsA-treated rats. Although CsA affects the activity of the MHC(1) promoter, it appears that its effect is not through direct binding of NFAT to sites on the promoter.

Animals↗
PubMed2004

Skeletal muscle hypertrophy in response to isometric, lengthening, and shortening training bouts of equivalent duration.

Movements generated by muscle contraction generally include periods of muscle shortening and lengthening as well as force development in the absence of external length changes (isometric). However, in the specific case of resistance exercise training, exercises are often intentionally designed to emphasize one of these modes. The purpose of the present study was to objectively evaluate the relative effectiveness of each training mode for inducing compensatory hypertrophy. With the use of a rat model with electrically stimulated (sciatic nerve) contractions, groups of rats completed 10 training sessions in 20 days. Within each training session, the duration of the stimulation was equal across the three modes. Although this protocol provided equivalent durations of duty cycle, the torque integral for the individual contractions varied markedly with training mode such that lengthening > isometric > shortening. The results indicate that the hypertrophy response did not track the torque integral with mass increases of isometric by 14%, shortening by 12%, and lengthening by 11%. All three modes of training resulted in similar increases in total muscle DNA and RNA. Isometric and shortening but not lengthening mode training resulted in increased muscle insulin-like growth factor I mRNA levels. These results indicate that relatively pure movement mode exercises result in similar levels of compensatory hypertrophy that do not necessarily track with the total amount of force generated during each contraction.

Animals↗
PubMed2003

Inhibition of MAP/ERK kinase prevents IGF-I-induced hypertrophy in rat muscles.

Insulin-like growth factor-I (IGF-I) has been shown to stimulate a hypertrophy response in skeletal muscles in vivo. In vitro studies have delineated two primary intracellular pathways that appear to mediate the effects of IGF-I in skeletal muscle: the Ras-ERK pathway and the phosphoinositide-3 kinase pathway. In vitro, the Ras pathway appears to regulate the mitogenic effects of IGF-I signaling, whereas the phosphoinositide-3 kinase pathway is associated with cellular differentiation. On the basis of the results from in vitro studies, we hypothesized that the coinfusion of both IGF-I and an inhibitor of the Ras pathway would result in some increase in muscle protein but an inhibition of cell proliferation. Our results show that 14 days of coinfusion of MAPK/ERK kinase inhibitor PD-098059 (PD) limited the phosphorylation of ERK and prevented IGF-I induced increases in protein (18%, P < 0.05 vs. 7%, not significant) or myofibrillar protein (23%, P < 0.01 vs. 5%, not significant). However, there were similar increases in indicators of cell proliferation (e.g., total DNA, 50 and 52%, P < 0.001) in both the IGF- and IGF+PD-infused muscles. The most notable impact on IGF-I signaling was a significant blunting of IGF-I induced increase in S6K1 phosphorylation by PD-98059 coinfusion ( approximately 5-fold, P < 0.001 vs. 3-fold, P < 0.01). These results suggest that there are interactions between the various pathways down stream of the IGF-I receptor that may behave differently in vivo than in myogenic cell lines in vitro.

Adaptation, Physiological↗
PubMed2003

Role of antisense RNA in coordinating cardiac myosin heavy chain gene switching.

A novel mechanism of regulation of cardiac alpha and beta myosin heavy chain gene by naturally occurring antisense transcription was elucidated via pre-mRNA analysis. Herein, we report the expression of an antisense beta myosin heavy chain RNA in the normal rodent myocardium. The pattern of expression of the antisense betaMHC RNA (beta RNA) under altered thyroid state and in diabetes directly correlates with that of the alpha pre-mRNA/mRNA, whereas it negatively correlates with the beta mRNA expression. Rapid amplification of the 5' end shows that this antisense transcript originates 2 kb downstream of the beta gene, and it is transcribed across the entire beta gene from the opposite strand. Our results demonstrate that the beta-alpha myosin heavy chain intergenic DNA possesses a bidirectional transcriptional activity, one direction transcribing the alpha gene, and the opposite direction transcribing the antisense beta RNA. This process turns on the alpha expression, and it simultaneously turns off that of the beta and thus coordinates alpha and beta expression in an opposite fashion. Comparative analyses of the intergenic DNA sequence across five mammalian species revealed a conserved region that is proposed to be a common regulatory region for the alpha and antisense beta promoter. This finding unravels the mechanism of cardiac alpha-beta gene switching and implicates the role of cardiac myosin gene organization with their function.

Animals↗