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Biomedical subjects

Priscilla M Clarkson

Publications and source records attributed to Priscilla M Clarkson.

At least 19 recordsLinked to original sources
PubMed2007

Alterations in mRNA expression and protein products following spinal cord injury in humans.

We examined the effects of spinal cord injury (SCI) on alterations in gene expression and respective protein products in human skeletal muscle 2 days and 5 days post-SCI. Biopsies were taken from skeletal muscle of 9 men and 1 woman (n = 10) (43.9 +/- 6.7 years) 2 days and 5 days post-SCI and from 5 healthy young men who served as controls (20.4 +/- 0.5 years). Global changes in gene expression were analysed using Affymetrix GeneChips on a subsample of subjects (n = 3). Candidate genes were then pursued via qRT-PCR. Western blotting (WB) was used to quantify protein products of candidate genes. Immunohistochemistry (IHC) was used to localize proteins. Groups of transcripts showing the greatest percentage of altered expression, the most robust fold-changes, and indicative of involvement of an entire pathway using the GeneChip included genes involved in the ubiquitin proteasome pathway (UPP), metallothionein function, and protease inhibition. qRT-PCR analysis confirmed increases in gene expression for UPP components (UBE3C, Atrogin-1, MURF1, and PSMD11), the metallothioneins (MT1A, MT1F, MT1H), and the protease inhibitor, SLPI (P < 0.05) at 2 days and 5 days post-SCI. Protein levels of the proteasome subunit (PSMD11) and the metallothioneins were increased 5 days post-SCI. Protein levels of UBE3C, Atrogin-1, MURF1 and SLPI were unchanged (P > 0.05). IHC showed increased staining for PSMD11 and the metallothioneins 5 days post-SCI, along the peripheral region of the cells. IHC also showed altered staining for Atrogin-1 at 5 days post-SCI along the membrane region. Thus, there was a profound increase in gene expression of UPP components, the metallothioneins, and the protease inhibitor, SLPI, within 5 days of SCI. Increased protein levels for PSMD11 and the metallothioneins 5 days post-SCI, specifically along the cell periphery, indicate that proteins in this region may be early targets for degradation post-SCI.

Adult↗
PubMed2006

Analysis of human skeletal muscle after 48 h immobilization reveals alterations in mRNA and protein for extracellular matrix components.

We examined the effects of 48 h of knee immobilization on alterations in mRNA and protein in human skeletal muscle. We hypothesized that 48 h of immobilization would increase gene expression and respective protein products for ubiquitin-proteasome pathway (UPP) components. Also, we used microarray analysis to identify novel pathways. Biopsies were taken from the vastus muscle of five men (20.4 +/- 0.5 yr) before and after 48-h immobilization. Global changes in gene expression were analyzed by use of Affymetrix GeneChips. Candidate genes were confirmed via quantitative RT-PCR. Western blotting (WB) was used to quantify protein products of candidate genes and to assess Akt pathway activation. Immunohistochemistry was used to localize proteins found to be altered when assessed via WB. The greatest percentage of genes showing altered expression with the GeneChip included genes involved in the UPP, metallothionein function, and extracellular matrix (ECM) integrity. Quantitative RT-PCR analysis confirmed increases in mRNA for UPP components [USP-6, small ubiquitin-related modifier (SUMO-1)] and the metallothioneins (MT2A, MT1F, MT1H, MT1X) and decreases in mRNA content for matrix metalloproteinases (MMP-28, TIMP-1) and ECM structural components [collagen III (COLIII) and IV (COLIV)]. Only phosphorylated Akt (Ser473, Thr308), COLIII and COLIV protein levels were significantly different postimmobilization (25, 10, 88, and 28% decrease, respectively). Immunohistochemistry confirmed WB showing decreased staining for collagens postimmobilization. Our results suggest that 48 h of immobilization increases mRNA content for components of the UPP and metallothionein function while decreasing mRNA and protein for ECM components as well as decreased phosphorylation of Akt.

Adult↗
PubMed2006

An assessment of statin safety by muscle experts.

The National Lipid Association's (NLA) Muscle Safety Expert Panel was charged with the duty of examining the definitions, causative factors, and management of statin myopathy. The Panel was asked to use its evidence-based findings to form recommendations in response to a series of specific questions posed by the Task Force. The panel was composed of a clinical cardiologist, an exercise physiologist and skeletal muscle expert, and an expert in preventive cardiology who also examined skeletal muscle complications of statin use.

Biopsy↗
PubMed2006

CK-MM autoantibodies: prevalence, immune complexes, and effect on CK clearance.

Although the blood level of creatine kinase (CK) is the most commonly used marker of muscle injury, there is marked interindividual variability in this measure. Part of this variability may be attributed to variability in the rate of CK clearance from the circulation. In this study, we assessed the possibility that CK-MM autoantibodies form immune complexes with CK following muscle injury and subsequently affect the CK clearance rate. Using an enzyme-linked immunosorbent assay, CK-MM autoantibodies were detected in all 25 human subjects studied but the levels varied greatly. Using protein A-sepharose, the percentage of the plasma CK activity found in immune complexes was determined to be correlated with the CK-MM autoantibody level at lower CK levels (<1,022 U/L). When CK-MM antibodies were administered to mice, plasma CK activity following a bolus CK injection was reduced by 11%-32%. We conclude that CK-MM autoantibodies can modulate the rate of CK clearance from the circulation. Thus, the relatively low blood CK levels seen in some individuals following injury may be attributed partly or entirely to an autoantibody-enhanced clearance of CK.

Adult↗
PubMed2006

Case report of exertional rhabdomyolysis in a 12-year-old boy.

INTRODUCTION: Exertional rhabdomyolysis has been well characterized, and many case reports exist. No cases of exertional rhabdomyolysis in young healthy children (preteen) have been published. CASE SUMMARY: Reviewed were the medical records of a 12-yr-old boy who participated in an indoor physical education class where excessive (>250) repetitive squat jumps were performed as punishment for talking in class. The boy, who reported intense muscle soreness in the thighs and dark urine 2 d postexercise, was brought to the emergency room by his parent. His serum creatine kinase (CK) was 92,115 U.L(-1) and urinalysis indicated the presence of blood and protein. He was transferred to another hospital that evening, admitted, and treated for 7 d. His serum CK rose to 244,006 U.L(-1) at 4 d postexercise. CONCLUSION: Although exertional rhabdomyolysis is rare in young children, it can occur when excessive exercise is spurred on by an adult.

Child↗
PubMed2006

Serum creatine kinase levels and renal function measures in exertional muscle damage.

PURPOSE: Serum creatine kinase (CK) levels are commonly used to judge the severity of muscle damage and to determine when to hospitalize patients who present with symptoms of exertional rhabdomyolysis in order to prevent renal failure. However, no CK standard exists because of the limited information available regarding exercise-induced CK elevation and renal function. This study determined the magnitude of CK elevation and the effect on renal function produced by exercise in a large subject group. METHODS: Blood samples were obtained from 203 volunteers who performed 50 maximal eccentric contractions of the elbow flexor muscles. The samples, taken before and 4, 7, and 10 d after exercise, were analyzed for markers of muscle damage (CK, myoglobin (Mb), lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase and for measures of renal function (creatinine, blood urea nitrogen, phosphorus, potassium, osmolality, and uric acid). RESULTS: All indicators of muscle damage increased significantly after exercise (P < 0.01). CK levels were 6420, 2100, and 311% above baseline on days 4, 7, and 10 after the exercise, respectively (P < 0.01), and Mb was 1137, 170, and 28% above baseline on days 4, 7, and 10 after exercise, respectively (P < 0.01). Of the 203 participants, 111 had CK values at 4 d postexercise > 2,000 U x L(-1) and 51 had values > 10,000 U x L(-1), levels used to diagnose myopathy (e.g., statin myositis) and rhabdomyolysis, respectively. There were no significant increases in any measure of renal function. Despite marked CK and Mb elevations in some subjects, none experienced visible myoglobinuria or required treatment for impaired renal function. CONCLUSIONS: Exertional muscle damage produced by eccentric exercise in healthy individuals can cause profound CK and Mb elevations without renal impairment.

Adolescent↗
PubMed2006

ACE ID genotype and the muscle strength and size response to unilateral resistance training.

PURPOSE: To examine associations among the angiotensin I-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism and the response to a 12-wk (2 d.wk) unilateral, upper-arm resistance training (RT) program in the trained (T, nondominant) and untrained (UT, dominant) arms. METHODS: Subjects were 631 (mean+/-SEM, 24.2+/-0.2 yr) white (80%) men (42%) and women (58%). The ACE ID genotype was in Hardy-Weinberg equilibrium with frequencies of 23.1, 46.1, and 30.8% for ACE II, ID, and DD, respectively (chi=1.688, P=0.430). Maximum voluntary contraction (MVC) and one-repetition maximum (1RM) assessed peak elbow flexor muscle strength. Magnetic resonance imaging measured biceps muscle cross-sectional area (CSA). Multiple variable and repeated-measures ANCOVA tested whether muscle strength and size differed at baseline and pre- to post-RT among T and UT and ACE ID genotype. RESULTS: Baseline muscle strength and size were greater in UT than T (P<0.001) and did not differ among ACE ID genotype in either arm (P >or= 0.05). In T, MVC increases were greater for ACE II/ID (22%) than DD (17%) (P<0.05), whereas 1RM (51%) and CSA (19%) gains were not different among ACE ID genotype pre- to post-RT (P >or= 0.05). In UT, MVC increased among ACE II/ID (7%) (P<0.001) but was similar among ACE DD (2%) pre- to post-RT (P >or= 0.05). In UT, 1RM (11%) and CSA (2%) increases were greater for ACE DD/ID than ACE II (1RM, 7%; CSA, -0.1%) (P<0.05). ACE ID genotype explained approximately 1% of the MVC response to RT in T and approximately 2% of MVC, 2% of 1RM, and 4% of CSA response in UT (P<0.05). CONCLUSION: ACE ID genotype is associated with the contralateral effects of unilateral RT, perhaps more so than with the muscle strength and size adaptations that result from RT.

Adult↗
PubMed2005

Changes in ubiquitin proteasome pathway gene expression in skeletal muscle with exercise and statins.

OBJECTIVE: Statins are safe medications but have side effects including myalgia and rhabdomyolysis. How statins provoke muscle damage is not known, but this effect is exacerbated by exercise. METHODS AND RESULTS: Healthy subjects took Atorvastatin (80 mg/daily) or placebo for 4 weeks. Biopsies of both vastus lateralis muscles were performed 8 hours after eccentric exercise (known to result in muscle soreness and damage) of the left leg at baseline and the right leg after statin/placebo treatment. Gene expression was determined using Affymetrix GeneChips, and selected genes confirmed by polymerase chain reaction (qRT-PCR). Atorvastatin had little effect on gene expression at rest. When combined with exercise, 56 genes were differentially expressed with 18% involved in the ubiquitin proteasome pathway (UPP) and 20% involved in protein folding and catabolism, and apoptosis. CONCLUSIONS: This is the first investigation to our knowledge to implicate involvement of the UPP in skeletal muscle in response to combined exercise and statin treatment, possibly explaining the onset of myalgia with exertion. Statins may alter the response of muscle to exercise stress by altering the action of the UPP, protein folding, and catabolism, disrupting the balance between protein degradation and repair.

Adolescent↗
PubMed2005

ACTN3 and MLCK genotype associations with exertional muscle damage.

Strenuous exercise results in damage to skeletal muscle that is manifested in delayed muscle pain, prolonged strength loss, and increases in muscle proteins in the blood, especially creatine kinase (CK) and myoglobin (Mb). Some individuals experience profound changes in these variables in response to standard laboratory exercise or recreational activities. We proposed that variations in genes coding for two myofibrillar proteins [alpha-actinin 3 (ACTN3) and myosin light chain kinase (MLCK)] may explain the large variability in the response to muscle-damaging exercise. We hypothesized that subjects with specific single nucleotide polymorphisms (SNPs) in ACTN3 and MLCK would show a greater loss in muscle strength and/or a greater increase in blood CK and Mb in response to eccentric exercise. Blood from 157 subjects who performed a standard elbow flexion eccentric exercise protocol was tested for association between genotypes of ACTN3 (1 SNP tested: R577X) and MLCK (2 SNPs tested: C49T and C37885A) and changes in blood CK and Mb and isometric strength. Subjects possessing the ACTN3-deficient genotype (XX) had lower baseline CK compared with the heterozygotes (P = 0.035). After the eccentric exercise, those subjects homozygous for the MLCK 49T rare allele had a significantly greater increase in CK and Mb (P < 0.01) compared with the heterozygotes, and those heterozygous for MLCK C37885A had a significantly greater increase in CK compared with the homozygous wild type (P < 0.05). There was only one subject homozygous for the rare MLCK 37885A allele. MLCK C37885A was also associated with postexercise strength loss (P < 0.05); the heterozygotes demonstrated greater strength loss compared with the homozygous wild type (CC). These results show that variations in genes coding for specific myofibrillar proteins influence phenotypic responses to muscle damaging exercise.

Actinin↗
PubMed2005

ACTN3 genotype is associated with increases in muscle strength in response to resistance training in women.

The alpha-actinin 3 (ACTN3) gene encodes a protein of the Z disk of myofibers, and a polymorphism of ACTN3 results in complete loss of the protein. The ACTN3 genotype (R577X) has been found to be associated with performance in Australian elite athletes (Yang N, MacArthur DG, Gulbin JP, Hahn AG, Beggs AH, Easteal S, and North K. Am J Hum Genet 73: 627-631, 2003). We studied associations between ACTN3 genotype and muscle size [cross-sectional area of the biceps brachii via magnetic resonance imaging (MRI)] and elbow flexor isometric (MVC) and dynamic [1-repetition maximum (1-RM)] strength in a large group of men (N = 247) and women (N = 355) enrolled in a 12-wk standardized elbow flexor/extensor resistance training program of the nondominant arm at one of eight study centers. We found no association between ACTN3 R577X genotype and muscle phenotype in men. However, women homozygous for the ACTN3 577X allele (XX) had lower baseline MVC compared with heterozygotes (P < 0.05) when adjusted for body mass and age. Women homozygous for the mutant allele (577X) demonstrated greater absolute and relative 1-RM gains compared with the homozygous wild type (RR) after resistance training when adjusted for body mass and age (P < 0.05). There was a trend for a dose-response with genotype such that gains were greatest for XX and least for RR. Significant associations were validated in at least one ethnic subpopulation (Caucasians, Asians) and were independent of training volume. About 2% of baseline MVC and of 1-RM strength gain after training were attributable to ACTN3 genotype (likelihood-ratio test P value, P = 0.01), suggesting that ACTN3 is one of many genes contributing to genetic variation in muscle performance and adaptation to exercise.

Actinin↗
PubMed2005

Variability in muscle size and strength gain after unilateral resistance training.

PURPOSE: This study assessed variability in muscle size and strength changes in a large cohort of men and women after a unilateral resistance training program in the elbow flexors. A secondary purpose was to assess sex differences in size and strength changes after training. METHODS: Five hundred eighty-five subjects (342 women, 243 men) were tested at one of eight study centers. Isometric (MVC) and dynamic strength (one-repetition maximum (1RM)) of the elbow flexor muscles of each arm and magnetic resonance imaging (MRI) of the biceps brachii (to determine cross-sectional area (CSA)) were assessed before and after 12 wk of progressive dynamic resistance training of the nondominant arm. RESULTS: Size changes ranged from -2 to +59% (-0.4 to +13.6 cm), 1RM strength gains ranged from 0 to +250% (0 to +10.2 kg), and MVC changes ranged from -32 to +149% (-15.9 to +52.6 kg). Coefficients of variation were 0.48 and 0.51 for changes in CSA (P = 0.44), 1.07 and 0.89 for changes in MVC (P < 0.01), and 0.55 and 0.59 for changes in CSA (P < 0.01) in men and women, respectively. Men experienced 2.5% greater gains for CSA (P < 0.01) compared with women. Despite greater absolute gains in men, relative increases in strength measures were greater in women versus men (P < 0.05). CONCLUSION: Men and women exhibit wide ranges of response to resistance training, with some subjects showing little to no gain, and others showing profound changes, increasing size by over 10 cm and doubling their strength. Men had only a slight advantage in relative size gains compared with women, whereas women outpaced men considerably in relative gains in strength.

Adult↗
PubMed2004

Effects of repeated creatine supplementation on muscle, plasma, and urine creatine levels.

The purpose of this case study was to examine the effects of repeated creatine administration on muscle phosphocreatine, plasma creatine, and urine creatine. One male subject (age, 32 years; body mass, 78.4 kg; height, 160 cm; resistance training experience, 15 years) ingested creatine (20 g.d(-1) for 5 days) during 2 bouts separated by a 30-day washout period. Muscle phosphocreatine was measured before and after supplementation. On day 1 of supplementation, blood samples were taken immediately before and hourly for 5 hours following ingestion of 5 g of creatine, and a pharmacokinetic analysis of plasma creatine was conducted. Twenty-four-hour urine collections were conducted before and for 5 days during supplementation. Muscle phosphocreatine increased 45% following the first supplementation bout, decreased 22% during the 30-day washout period, and increased 25% following the second bout. There were no meaningful differences in plasma creatine pharmacokinetic parameters between bouts 1 and 2. Total urine creatine losses during supplementation were 63.2 and 63.4 g during bouts 1 and 2, respectively. The major findings were that (a) a 30-day washout period is insufficient time for muscle phosphocreatine to return to baseline following creatine supplementation but is sufficient time for plasma and urine creatine levels to return to presupplementation values; (b) postsupplementation muscle phosphocreatine levels were similar following bouts 1 and 2 despite 23% higher presupplementation muscle phosphocreatine before bout 2; and (c) the increased muscle phosphocreatine that persisted throughout the 30-day washout period corresponded with maintenance of increased body mass (+2.0 kg). Athletes should be aware that the washout period for muscle creatine to return to baseline levels may be longer than 30 days in some individuals, and this may be accompanied by a persistent increase in body mass.

Adult↗
PubMed2003

Molecular responses of human muscle to eccentric exercise.

We examined the effect of eccentric exercise on the transcriptome of skeletal muscle in three male human volunteers who performed 300 concentric contractions with one leg and 300 eccentric contractions with the opposite leg. Vastus lateralis muscle biopsies were taken from both legs at 4-8 h after exercise, and expression was profiled by using 12000 gene Affymetrix U95Av2 microarrays. We found a high concordance of expression responses to eccentric contractions between our human and rat data from a previous study (Chen YW, Nader GA, Baar KR, Fedele MJ, Hoffman EP, and Esser KA. J Physiol 545: 27-41, 2002) ( approximately 50% of gene expression changes shared between species). Potential human-specific changes included greater inflammatory responses [chemokine (C-C motif) ligand 2, C/EBP delta, and IL-1 receptor] and vascular remodeling (tenascin C and lipocortin II). Induction of c-fos and lipocortin II were confirmed at the protein level, with c-fos localized to myofiber nuclei and lipocortin II to intramuscular capillaries. We also confirmed the eccentric-induced expression of six transcripts by quantitative RT-PCR (cardiac ankyrin-repeated protein, chemokine ligand 2, CCAAT/enhancer binding protein delta, IL-1 receptor, tenascin C, and cysteine-rich angiogenic inducer 61). These data provide the first characterization of the transcriptional response of skeletal muscle to eccentric exercise in humans and represent a preliminary step in understanding the molecular processes underlying muscle remodeling (including a new focus on rapid changes in the capillary bed) and inflammatory responses after damaging lengthening contractions.

Adult↗
PubMed2003

Oxidative stress, exercise, and antioxidant supplementation.

Cells continuously produce free radicals and reactive oxygen species (ROS) as part of metabolic processes. These free radicals are neutralized by an elaborate antioxidant defense system consisting of enzymes such as catalase, superoxide dismutase, glutathione peroxidase, and numerous non-enzymatic antioxidants, including vitamins A, E and C, glutathione, ubiquinone, and flavonoids. Exercise can produce an imbalance between ROS and antioxidants, which is referred to as oxidative stress. Dietary antioxidant supplements are marketed to and used by athletes as a means to counteract the oxidative stress of exercise. Whether strenuous exercise does, in fact, increase the need for additional antioxidants in the diet is not clear. This review examines the markers used to determine oxidative stress in blood and muscle samples (e.g. lipid peroxidation, expired pentane, malondialdehyde (MDA), F2-isoprostanes, congugated dienes, and 8-hydroxy-2'-deoxyguanosine (8-OhdG)), the changes in oxidative stress markers induced by exercise, and whether athletes require antioxidant supplements.

Antioxidants↗
PubMed2003

Neuromuscular variables affecting the magnitude of force loss after eccentric exercise.

The aim of this study was to examine neuromuscular variables contributing to differences in force loss after participants were exposed to the same relative bout of eccentric exercise. Thirty-six males performed 50 maximal eccentric contractions of the elbow flexors and were stratified into high responders (n = 10) and low responders (n = 10) based on force loss 36 h after exercise. Maximal voluntary isometric contractions (MVCs) and electromyography (EMG) were measured at baseline and 36 h after exercise. During eccentric exercise, mean peak torque, mean end-range torque from the final 25% of each trial and total angular impulse were computed over 25 contractions in each of two bouts. The slope of the change in these values for each 25 eccentric contractions was calculated for each participant using linear regression. At baseline, MVC was not different between groups (low responders: 97.0 +/- 9.6 N x m; high responders: 82.7 +/- 6.4 N x m; P = 0.08). High responders demonstrated a 68% (range 62-78%) reduction in MVC and low responders a 39% (29-48%) reduction after exercise. Peak torque, end-range torque and total angular impulse were 13%, 40% and 33% higher, respectively, in the low than in the high responders (peak torque: P = 0.0002; end-range torque: P < 0.0001; total angular impulse: P < 0.001). The rate of decline in peak torque slope was greater in high than in low responders (P = 0.044). In conclusion, lower peak torque, end-range torque and total angular impulse during eccentric contractions and a greater peak torque slope may identify high responders to eccentric exercise.

Adult↗