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OBJECTIVES: To determine the influence of angiotensinogen (AGT) A-20C, M235 T, and angiotensin II type 1 receptor (AGTR1) A1166C genotypes on resting blood pressure (BP) response to strength training (ST) in older men and women. DESIGN: Prospective intervention study with retrospective genotyping. SETTING: University of Maryland Exercise Physiology Laboratory. PARTICIPANTS: Seventy sedentary, healthy older men (n=34) and women (n=36). INTERVENTION: Approximately 23 weeks of ST performed 3 days per week. MEASUREMENTS: Resting BP was measured on six separate occasions before and after ST for each subject. AGT and AGTR1 genotyping was performed retrospectively from each subject's genomic deoxyribonucleic acid. RESULTS: Systolic BP decreased in C-allele carriers at the AGT A-20C locus with ST (122+/-1 to 116+/-2 mmHg, P<.05), which was significantly greater than the decrease in the A homozygotes (126+/-1 to 123+/-1 mmHg, P<.05). At the AGTR1 A1166C locus, diastolic BP decreased to a greater extent in the C-allele carriers (76+/-1 to 70+/-2 mmHg, P<.05) than in the A homozygotes (75+/-1 to 72+/-1 mmHg, P<.05). CONCLUSION: The AGT A-20C and AGTR1 A1166C genotypes may influence resting BP response to ST, such that C-allele carriers at each of these loci reduce their resting BP in response to ST to a greater extent than A homozygotes. [ABSTRACT FROM AUTHOR]

Objective: This pilot trial examined the effects of a combined intervention of mindfulness meditation followed by aerobic walking exercise compared with a control condition in chronic low back pain patients. We hypothesized that meditation before exercise would reduce disability, pain, and anxiety by increasing mindfulness prior to physical activity compared with an audiobook control group., Participants: Thirty-eight adults completed either meditation and exercise treatment (MedExT) (n=18) or an audiobook control condition (n=20)., Setting: Duquesne University Exercise Physiology Laboratory., Design: A pilot, assessor-blinded, randomized controlled trial., Methods: Over a 4-week period, participants in the MedExT group performed 12-17 minutes of guided meditation followed by 30 minutes of moderate-intensity walking exercise 5 days per week. Measures of disability, pain, mindfulness, and anxiety were taken at baseline and postintervention. Pain perception measurements were taken daily., Results: Compared with the control group, we observed larger improvements in disability in the MedExT intervention, although the changes were modest and not statistically significant (mean between-group difference, -1.24; 95% confidence interval [CI], -3.1 to 0.6). For secondary outcome measures, MedExT increased mindfulness (within-group) from pre-intervention to postintervention (P=0.0141). Additionally, mean ratings of low back pain intensity and unpleasantness significantly improved with time for the MedExT group compared with that of the control group, respectively (intensity P=0.0008; unpleasantness P=0.0022)., Conclusion: . Overall, 4 weeks of MedExT produced suggestive between-group trends for disability, significant between-group differences for measures of pain, and significant within-group increases in mindfulness., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Knowledge of efficacious dosing respective to exercise type and pain condition is extremely limited in the literature. This study aimed to determine the impact of dose of moderate intensity treadmill walking on experimentally-induced pain in healthy human participants. Forty females were divided into 4 groups: control (no exercise), low dose exercise (3×/wk), moderate dose exercise (5×/wk) or high dose exercise (10×/wk). Over a 7-day period, subjects performed treadmill walking during assigned exercise days. Both qualitative and quantitative measures of pain were measured at baseline, during the trial, and 24 hrs post-final intervention session via sensitivity thresholds to painful thermal and painful pressure stimulation. Significant effects of treatment were found post-intervention for constant pressure pain intensity (p = 0.0016) and pain unpleasantness ratings (p = 0.0014). Post-hoc tests revealed significant differences between control and moderate and control and high dose groups for constant pressure pain intensity (p = 0.0015), (p = 0.0094), respectively and constant pressure pain unpleasantness (p = 0.0040), (p = 0.0040), respectively. Moderate and high dose groups had the greatest reductions in ratings of pain, suggesting that our lowest dose of exercise was not sufficient to reduce pain and that the moderate dose of exercise may be a sufficient starting dose for exercise-based adjuvant pain therapy.

Cancer cachexia, an unintentional body weight loss due to cancer, affects patients' survival, quality of life, and response to chemotherapy. Although exercise training is a promising intervention to prevent and treat cancer cachexia, our mechanistic understanding of cachexia's effect on contraction-induced muscle adaptation has been limited to the examination of male mice. Because sex can affect muscle regeneration and response to contraction in humans and mice, the effect of cachexia on the female response to eccentric contraction warrants further investigation., Purpose: The purpose of this study was to determine whether high-frequency electric stimulation (HFES) could attenuate muscle mass loss during the progression of cancer cachexia in female tumor-bearing mice., Methods: Female wild-type (WT) and Apc (Min) mice (16-18 wk old) performed either repeated bouts or a single bout of HFES (10 sets of 6 repetitions, ~22 min), which eccentrically contracts the tibialis anterior (TA) muscle. TA myofiber size, oxidative capacity, anabolic signaling, and catabolic signaling were examined., Results: Min had reduced TA muscle mass and type IIa and type IIb fiber sizes compared with WT. HFES increased the muscle weight and the mean cross-sectional area of type IIa and type IIb fibers in WT and Min mice. HFES increased mTOR signaling and myofibrillar protein synthesis and attenuated cachexia-induced AMPK activity. HFES attenuated the cachexia-associated decrease in skeletal muscle oxidative capacity., Conclusion: HFES in female mice can activate muscle protein synthesis through mTOR signaling and repeated bouts of contraction can attenuate cancer-induced muscle mass loss.

Objective: Increasing evidence purports exercise as a first-line therapeutic for the treatment of nearly all forms of chronic pain. However, knowledge of efficacious dosing respective to treatment modality and pain condition is virtually absent in the literature. The purpose of this analysis was to calculate the extent to which exercise treatment shows dose-dependent effects similar to what is seen with pharmacological treatments., Methods: A recently published comprehensive review of exercise and physical activity for chronic pain in adults was identified in May 2017. This report reviewed different physical activity and exercise interventions and their effectiveness in reducing pain severity and found overall modest effects of exercise in the treatment of pain. We analyzed this existing data set, focusing specifically on the dose of exercise intervention in these studies. We re-analyzed data from 75 studies looking at benefits of time of exercising per week, frequency of exercise per week, duration of intervention (in weeks), and estimated intensity of exercise., Results: Analysis revealed a significant positive correlation with exercise duration and analgesic effect on neck pain. Multiple linear regression modeling of these data predicted that increasing the frequency of exercise sessions per week is most likely to have a positive effect on chronic pain patients., Discussion: Modest effects were observed with one significant correlation between duration and pain effect for neck pain. Overall, these results provide insufficient evidence to conclude the presence of a strong dose effect of exercise in pain, but our modeling data provide tes predictions that can be used to design future studies to explicitly test the question of dose in specific patient populations., Competing Interests: The authors have declared that no competing interests exist.

Objective: This study investigates 4 single-nucleotide polymorphisms [Apolipoprotein E (APOE), APOE promoter, catechol-O-methyl transferase (COMT), and dopamine D2 receptor] that have been implicated in concussion susceptibility and/or cognitive ability in collegiate student-athletes., Design: Cross-sectional study., Setting: Neuroscience laboratory at Elon University., Participants: Two hundred fifty division I collegiate student-athletes (66 women, 184 men) from various sports., Intervention: All participants completed Immediate Postconcussion Assessment and Cognitive Testing (ImPACT) testing at baseline concussion testing and had a buccal swab taken for DNA for genotyping., Main Outcome Measures: Self-reported history of concussions and neurocognitive performance were taken from ImPACT., Results: Individuals carrying an ε4 allele in their APOE gene had a significantly slower reaction time (P = 0.001). Individuals homozygous for the Val allele of the COMT gene showed significantly worse impulse control scores (P = 0.014). None of the genotypes were able to predict self-reported concussion history in collegiate student-athletes., Conclusions: These results indicate that certain genotypes may influence performance on cognitive testing at baseline and that the APOE genotypes may not influence concussion susceptibility as suggested by past studies.

Duchenne muscular dystrophy is a lethal genetic disease of muscle wasting for which there is no cure. In healthy muscle, structure and function improve dramatically with exercise. In patients with dystrophy, little is known about the effects of exercise. As contemporary therapies rapidly progress and patients become more active, there is a need to understand the effects of exercise.

Objective: Determine whether therapeutic ultrasound (TUS) delivered in a continuous mode reduces pain perception after muscle injury., Design: Randomized, double-blind trial., Setting: Institutional laboratory., Participants: Twenty young healthy participants (11 females; 9 males; mean age ± SD, 24.1 ± 3.7 years)., Intervention: All subjects performed 50 maximal eccentric contractions of the biceps brachii on a Biodex dynamometer. Criterion measures of isometric force production and serum creatine kinase (CK) activity confirmed tissue damage. Both groups received either TUS or sham treatment everyday starting 24 hours after muscle damage. Muscle soreness and pain were assessed at baseline, 48 hours postdamage, and every other day for 8 days., Main Outcome Measures: Muscle pain was assessed with a battery of tests: visual analog scale (VAS), Short-form McGill Pain Questionnaire-2, joint angle changes, and mechanical pressure threshold., Results: Confirmation of damage occurred with baseline compared to 48 hours after damage of isometric peak torque (N·m; P < 0.01) and CK activity (IU/I; P = 0.03). Our results showed significant treatment group differences in VAS (P = 0.01) and mechanical pressure threshold (P = 0.02) after the third TUS treatment in the distal bicep brachii region., Conclusions: Continuous TUS reduced pain perception and increased mechanical pressure threshold in the biceps brachii after muscle damage, specifically near the distal musculotendinous junction.

Concussions are occurring at alarming rates in the United States and have become a serious public health concern. The CDC estimates that 1.6 to 3.8 million concussions occur in sports and recreational activities annually. Concussion as defined by the 2013 Concussion Consensus Statement "may be caused either by a direct blow to the head, face, neck or elsewhere on the body with an 'impulsive' force transmitted to the head." Concussions leave the individual with both short- and long-term effects. The short-term effects of sport related concussions may include changes in playing ability, confusion, memory disturbance, the loss of consciousness, slowing of reaction time, loss of coordination, headaches, dizziness, vomiting, changes in sleep patterns and mood changes. These symptoms typically resolve in a matter of days. However, while some individuals recover from a single concussion rather quickly, many experience lingering effects that can last for weeks or months. The factors related to concussion susceptibility and the subsequent recovery times are not well known or understood at this time. Several factors have been suggested and they include the individual's concussion history, the severity of the initial injury, history of migraines, history of learning disabilities, history of psychiatric comorbidities, and possibly, genetic factors. Many studies have individually investigated certain factors both the short-term and long-term effects of concussions, recovery time course, susceptibility and recovery. What has not been clearly established is an effective multifaceted approach to concussion evaluation that would yield valuable information related to the etiology, functional changes, and recovery. The purpose of this manuscript is to show one such multifaceted approached which examines concussions using computerized neurocognitive testing, event related potentials, somatosensory perceptual responses, balance assessment, gait assessment and genetic testing.

Introduction: Duchenne muscular dystrophy (DMD) is a lethal genetic disease caused by mutations in the dystrophin gene resulting in chronic muscle damage, muscle wasting, and premature death. Utrophin is a dystrophin protein homologue that increases dystrophic muscle function and reduces pathology. Currently, no treatments that increase utrophin protein expression exist. However, exercise increases utrophin mRNA expression in healthy humans. Therefore, the purpose was to determine whether exercise increases utrophin protein expression in dystrophic muscle., Methods: Utrophin protein was measured in the quadriceps and soleus muscles of mdx mice after 12 weeks of voluntary wheel running exercise or sedentary controls. Muscle pathology was measured in the quadriceps., Results: Exercise increased utrophin protein expression 334 ± 63% in the quadriceps relative to sedentary controls. Exercise increased central nuclei 4 ± 1% but not other measures of pathology., Conclusions: Exercise may be an intervention that increases utrophin expression in patients with DMD., (Copyright © 2013 Wiley Periodicals, Inc.)

Patients with Duchenne muscular dystrophy (DMD) have reduced muscle function due to chronic muscle damage, inflammation, oxidative stress, and reduced oxidative capacity. Resveratrol reduces inflammation and oxidative stress, and increases oxidative capacity in other disease models. The purpose of this study was to determine the effects of resveratrol on muscle function, muscle pathology, and oxidative capacity in young mdx mice. For this, 4- to 5-week-old male mdx mice were randomized into control or resveratrol-treated groups and given resveratrol (100 mg/kg body mass) or an equal volume of water by gavage every other day for 8 weeks. Muscle function was assessed pre- and post-treatment. Central nucleation, total immune cell infiltrate, oxidative stress, and oxidative capacity were measured post-treatment. Resveratrol mediated substantial improvements in rotarod performance and in-situ peak tension by 53% and 17%, respectively, and slight improvements in central nucleation and oxidative stress. Resveratrol did not affect total immune cell infiltrate at 12 weeks of age, and had no effect on oxidative capacity. Resveratrol improves muscle function in mdx mice despite small changes in muscle pathology. The likely mechanism is a resveratrol-mediated reduction in immune cell infiltrate at the early stages of this disease, as previously reported by our laboratory.

Aim: Six1 is necessary for the genesis of several tissues, but in adults, it is expressed primarily in skeletal muscle where its function is unclear. Overexpression of Six1 with a cofactor in skeletal muscle causes slow-to-fast fibre-type transition. We sought to characterize the effects of a physiologically relevant Six1 knockdown., Methods: The tibialis anterior (TA) muscles of C57BL/6 mice were electroporated with Six1 knockdown vector (siRNA) or empty vector. Muscles were collected at 2 or 14 days after transfection for Six1 and myosin heavy chain (MHC) expression analysis. C2C12 mouse myoblasts were grown in standard conditions. Cells were cotransfected with MHC promoter vectors and Six1 expression vectors. Cells were harvested after 4 days of differentiation., Results: In vivo, the Six1 siRNA caused a decreased expression of Six1,1.8-fold (±0.1, P < 0.05). With decreased Six1, MHC IIB expression decreased 2.7-fold (±0.7, P = 0.04). Proportion of muscle fibres expressing MHC IIB decreased (45.3 ± 4.8% vs. 65.1 ± 7.3% in control group, P = 0.04), and total area expressing MHC IIB decreased with decreased Six1 (59.6 ± 4.3% vs. 75.2 ± 5.4% in control group, P < 0.05). Decreased Six1 increased MHC IIA expression 1.9-fold (±0.3, P = 0.04). In vitro, Six1 overexpression increased promoter activation of MHC IIB 2.9-fold (±0.3, P < 0.01). Six1 knockdown repressed MHC IIB promoter 2.9-fold (±0.1, P < 0.05) and MHC IIX 3.7-fold (±0.08, P < 0.01)., Conclusion: Six1 knockdown caused a fast-to-slow shift in MHC isoform, and this was confirmed by promoter activity of MHC genes. Six1 may ultimately control the contractile and metabolic properties that define muscle fibre phenotype., (© 2013 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Both isotonic and isokinetic eccentric muscle contractions are commonly used in muscle research laboratories to induce muscle damage, yet, the muscle damage outcomes between these 2 modes of eccentric contraction have not been compared. The purpose of this study was to compare modes of contraction for differences in muscle damage. 16 men were placed in the isotonic (IT: 110% of maximal isometric torque) or the isokinetic (IK: 120°/s) group, with each group performing 200 eccentric muscle actions of the knee extensors. Isometric peak torque, perceived soreness and CK activity were measured immediately pre and post exercise, and 48-h post exercise. Mean total work (~1700 J) and peak torque per set (~265 Nm) decreased over the 200 repetitions (p<0.01), and was not different between groups. Damage markers changed 48-h post exercise (p<0.05): peak isometric torque (-13%), creatine kinase activity (+200%) and self-perceived muscular soreness (+4 unit change). Significant group×time interactions (p<0.01) indicated that peak isometric torque was 22% lower, and creatine kinase and self-perceived muscular soreness were 330% and 3 unit difference higher in the IT as compared to the IK groups, 48-h post exercise. When equating for total work, skeletal muscle damage markers are higher during IT vs. IK modes. This reflects differences inherent in contraction type and suggests that this should be taken into account during physical rehabilitation., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background & Aims: Duchenne muscular dystrophy (DMD) is a lethal genetic disease with no cure. Reducing inflammation or increasing utrophin expression can alleviate DMD pathology. Resveratrol can reduce inflammation and activate the utrophin promoter. The aims of this study were to identify an active dose of resveratrol in mdx mice and examine if this dose decreased inflammation and increased utrophin expression., Methods: 5-week old mdx mice were given 0, 10, 100, or 500 mg/kg of resveratrol everyday for 10 days. Sirt1 was measured by qRT-PCR and used to determine the most active dose. Muscle inflammation was measured by H&E staining, CD45 and F4/80 immunohistochemistry. IL-6, TNFα, PGC-1α, and utrophin gene expression were measured by qRT-PCR. Utrophin, Sirt1, and PGC-1α protein were quantified by western blot., Results: The 100 mg/kg dose of resveratrol, the most active dose, increased Sirt1 mRNA 60 ± 10% (p < 0.01), reduced immune cell infiltration 21 ± 6% (H&E) and 42 ± 8% (CD45 immunohistochemistry (p < 0.05)), reduced macrophage infiltration 48 ± 10% (F4/80 immunohistochemistry (p < 0.05)), and increased IL-6, PGC-1α, and utrophin mRNA 247 ± 77%, 27 ± 17%, and 43 ± 23% respectively (p ≤ 0.05). Utrophin, Sirt1, and PGC-1α protein expression did not change., Conclusions: Resveratrol may be a therapy for DMD by reducing inflammation., (Copyright © 2012 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Six1 is a transcription factor that, along with cofactors (Eya1, Eya3, and Dach2), regulates skeletal muscle fiber-type and development. SIX1 (human) gene expression decreases after overload, but the time course of Six1 expression, if protein is affected, and if the response differs between muscles with differing phenotypes, is not known. Our purpose was to examine Six1 gene and protein expression and co-factor gene expression during the initiation of muscle overload, and determine if the muscle phenotype altered this response. The plantaris and soleus were functionally overloaded by synergistic ablation of the gastrocnemius, and Six1 gene and protein, and Six1 cofactor gene expression was measured. Six1 gene expression decreased at 1 day of overload 48 ± 9 and 47 ± 20 % (p < 0.01) in the plantaris and soleus. After 3 days of overload, Six1 protein expression increased 73 ± 17 and 168 ± 57 % in the plantaris and soleus (p < 0.05). After 1 day of overload, Dach2 gene expression decreased 56 ± 9 and 35 ± 3 % in both muscles (p < 0.001), while Eya1 decreased 33 ± 5 % only in the soleus (p < 0.01). Eya3 gene expression increased 127 ± 26 % (p < 0.05) and 76 ± 16 % (p < 0.05) in the plantaris and soleus, while Dach2 gene expression decreased 71 ± 4 % (p < 0.05) in the soleus after 3 days of overload. Six1 and Six1 co-factor expression is responsive to muscle overload in both fast and slow muscles. This indicates that this molecular program may affect overload adaptation regardless of muscle phenotype.

Background: Muscle protein turnover regulation during cancer cachexia is being rapidly defined, and skeletal muscle mitochondria function appears coupled to processes regulating muscle wasting. Skeletal muscle oxidative capacity and the expression of proteins regulating mitochondrial biogenesis and dynamics are disrupted in severely cachectic ApcMin/+ mice. It has not been determined if these changes occur at the onset of cachexia and are necessary for the progression of muscle wasting. Exercise and anti-cytokine therapies have proven effective in preventing cachexia development in tumor bearing mice, while their effect on mitochondrial content, biogenesis and dynamics is not well understood. The purposes of this study were to 1) determine IL-6 regulation on mitochondrial remodeling/dysfunction during the progression of cancer cachexia and 2) to determine if exercise training can attenuate mitochondrial dysfunction and the induction of proteolytic pathways during IL-6 induced cancer cachexia., Methods: ApcMin/+ mice were examined during the progression of cachexia, after systemic interleukin (IL)-6r antibody treatment, or after IL-6 over-expression with or without exercise. Direct effects of IL-6 on mitochondrial remodeling were examined in cultured C2C12 myoblasts., Results: Mitochondrial content was not reduced during the initial development of cachexia, while muscle PGC-1α and fusion (Mfn1, Mfn2) protein expression was repressed. With progressive weight loss mitochondrial content decreased, PGC-1α and fusion proteins were further suppressed, and fission protein (FIS1) was induced. IL-6 receptor antibody administration after the onset of cachexia improved mitochondrial content, PGC-1α, Mfn1/Mfn2 and FIS1 protein expression. IL-6 over-expression in pre-cachectic mice accelerated body weight loss and muscle wasting, without reducing mitochondrial content, while PGC-1α and Mfn1/Mfn2 protein expression was suppressed and FIS1 protein expression induced. Exercise normalized these IL-6 induced effects. C2C12 myotubes administered IL-6 had increased FIS1 protein expression, increased oxidative stress, and reduced PGC-1α gene expression without altered mitochondrial protein expression., Conclusions: Altered expression of proteins regulating mitochondrial biogenesis and fusion are early events in the initiation of cachexia regulated by IL-6, which precede the loss of muscle mitochondrial content. Furthermore, IL-6 induced mitochondrial remodeling and proteolysis can be rescued with moderate exercise training even in the presence of high circulating IL-6 levels.

Background: IL-6 is a pleiotropic cytokine that modulates inflammatory responses and plays critical roles in muscle maintenance and remodeling. In the mouse model (mdx) of Duchenne Muscular Dystrophy, IL-6 and muscle inflammation are elevated, which is believed to contribute to the chronic inflammation and failure of muscle regeneration in DMD. The purpose of the current study was to examine the effect of blocking IL-6 signaling on the muscle phenotype including muscle weakness and pathology in the mdx mouse., Methods: A monoclonal antibody against the IL-6 receptor (IL-6r mAb) that blocks local and systemic IL-6 signaling was administered to mdx and BL-10 mice for 5 weeks and muscle function, histology, and inflammation were examined., Results: IL-6r mAb treatment increased mdx muscle inflammation including total inflammation score and ICAM-1 positive lumens in muscles. There was no significant improvement in muscle strength nor muscle pathology due to IL-6r mAb treatment in mdx mice., Conclusions: These results showed that instead of reducing inflammation, IL-6 signaling blockade for 5 weeks caused an increase in muscle inflammation, with no significant change in indices related to muscle regeneration and muscle function. The results suggest a potential anti-inflammatory instead of the original hypothesized pro-inflammatory role of IL-6 signaling in the mdx mice.

The CA-repeat polymorphism in the insulin-like growth factor 1 (IGF1) gene promoter region has been associated with strength and circulating IGF-I protein levels. The purpose of the study was to determine if the IGF1 CA-repeat polymorphism influences muscle power at baseline and in response to ST in older adults. Knee extensor peak power (PP) was measured at 50, 60, and 70% of 1-RM strength before and after 10 weeks of unilateral knee extensor ST in older adults, aged 50-85 years, to determine the changes in absolute and relative PP with ST. Subjects (N = 114) were genotyped for the IGF1 CA-repeat polymorphism and grouped as homozygous for the 192 allele, heterozygous, or non-carriers of the 192 allele. The 192 homozygotes had significantly lower baseline PP at 50, 60, and 70% of 1-RM strength than the non-carriers when age, sex, and baseline fat-free mass were covaried (all P < 0.05). This same relationship was observed when the highest PP within these ranges was compared (e.g., 317.6 ± 13.5 for 192 homozygotes and 380.2 ± 16.3 for non-carriers of the 192 allele, P < 0.05). Both absolute and relative PP increased significantly with ST in all genotype groups as expected, but there were no significant relationships among IGF1 genotypes and any of the PP changes. Despite a significant relationship between IGF1 genotype and knee extensor peak power at baseline, IGF1 genotype does not appear to influence changes in knee extensor peak power with ST.

Skeletal muscle undergoes numerous morphological changes from early adulthood to old age including muscle size, configuration, and structure. This review discusses these changes, considers the limitations in interpreting studies, addresses the potential health implications, and describes some mechanisms and interventions to ameliorate aging-related changes in skeletal muscle. Discussion in each section focuses on measurement and analysis techniques of muscle morphology, limitations of human research, and the discussion uses animal work to support findings in humans. We examine the discrepancies in the study of fiber type distribution with age, and special emphasis is given to two topics: fiber-type distribution and intra- and intercellular fat. Finally, training adaptations and health implications are briefly discussed. The focus of the current review is the morphological changes that occur in skeletal muscle during the normal aging process, with emphasis on human studies.

Background: Animal models of skeletal muscle damage and repair demonstrate that therapeutic ultrasound (TUS) enhances muscle force recovery after damage, increases satellite cell proliferation, and decreases insulin-like growth factor (IGF)-1 splice variant (mechano growth factor) gene expression. However, these effects have not been verified in humans., Purpose: This study was undertaken to examine the 3 known splice variants of the IGF-1 gene in human skeletal muscle after damage and TUS treatment., Study Design: Controlled laboratory study., Methods: Sixteen healthy men (18-29 years of age), physically active, were randomized to either a control (CON) or experimental group (EXP). The EXP group underwent 200 lengthening contractions (muscle damage) of the quadriceps of both legs, 48 hours before TUS. Both groups received TUS, delivered for 10 minutes on a standardized area of the vastus lateralis of only 1 leg (1.0 MHz, 1.5 W/cm(2)). Bilateral muscle biopsy samples were taken from all participants, 6 hours after TUS. Total RNA was extracted, and quantitative real-time polymerase chain reaction conducted for each IGF-1 splice variant., Results: Muscle damage was confirmed by a decrease in the isometric peak torque and increase in creatine kinase activity levels 48 hours after damage (P < .01). After muscle damage, gene expression of total IGF-1 and 2 IGF-1 splice variants increased. Therapeutic ultrasound induced significant increase in IGF-1Eb gene expression in undamaged muscle (1.4 ± 0.2-fold, P < 0.01). In damaged skeletal muscle, no significant change in gene expression attributable to TUS was determined., Conclusion: Insulin-like growth factor-1 splice variants are differentially regulated in human skeletal muscle in response to exercise-induced muscle damage and TUS treatment. A single treatment of TUS in damaged muscle induces no change in the gene expression of the 3 IGF-1 splice variants in humans. In contrast, in undamaged skeletal muscle, TUS significantly increased IGF-1Eb splice variant gene expression., Clinical Relevance: These findings suggest that TUS may have additional therapeutic uses beyond its current common practice but may not be effective for muscle injury treatment in a young, healthy population.

Muscle wasting that occurs with cancer cachexia is caused by an imbalance in the rates of muscle protein synthesis and degradation. The Apc(Min/+) mouse is a model of colorectal cancer that develops cachexia that is dependent on circulating IL-6. However, the IL-6 regulation of muscle protein turnover during the initiation and progression of cachexia in the Apc(Min/+) mouse is not known. Cachexia progression was studied in Apc(Min/+) mice that were either weight stable (WS) or had initial (≤5%), intermediate (6-19%), or extreme (≥20%) body weight loss. The initiation of cachexia reduced %MPS 19% and a further ∼50% with additional weight loss. Muscle IGF-1 mRNA expression and mTOR targets were suppressed with the progression of body weight loss, while muscle AMPK phosphorylation (Thr 172), AMPK activity, and raptor phosphorylation (Ser 792) were not increased with the initiation of weight loss, but were induced as cachexia progressed. ATP dependent protein degradation increased during the initiation and progression of cachexia. However, ATP independent protein degradation was not increased until cachexia had progressed beyond the initial phase. IL-6 receptor antibody administration prevented body weight loss and suppressed muscle protein degradation, without any effect on muscle %MPS or IGF-1 associated signaling. In summary, the %MPS reduction during the initiation of cachexia is associated with IGF-1/mTOR signaling repression, while muscle AMPK activation and activation of ATP independent protein degradation occur later in the progression of cachexia. IL-6 receptor antibody treatment blocked cachexia progression through the suppression of muscle protein degradation, while not rescuing the suppression of muscle protein synthesis. Attenuation of IL-6 signaling was effective in blocking the progression of cachexia, but not sufficient to reverse the process.

Previous studies have reported associations of polymorphisms in the IGF1 gene with phenotypes of body composition (BC). The purpose of this study was to identify phenotypes of BC and physical function that were associated with the IGF1 promoter polymorphism (rs35767, -C1245T). Subjects from the Health, Aging, and Body Composition Study, white males and females (n = 925/836) and black males and females (533/705) aged 70-79 years were genotyped for the polymorphism. Phenotypes of muscle size and function, bone mineral density, and BC were analyzed for associations with this polymorphism. To validate and compare these findings, a cohort of young (mean age = 24.6, SD = 5.9) white men and women (n = 173/296) with similar phenotypic measurements were genotyped. An association with BC was identified in elderly females when significant covariates (physical activity, age, smoking status, body mass index) were included. White women with C/C genotype had 3% more trunk fat and 2% more total fat than those with C/T (P < 0.05). Black women with C/C genotype had 3% less total lean mass and 3% less muscle mass than their T/T counterparts (P < 0.05). Associations were identified with muscle strength in white women (P < 0.01) that were in agreement with the C/C genotype having lower muscle function. Thus, in an elderly population but not a young population, a polymorphism in the IGF1 gene may be predictive of differences in body composition, primarily in black females.

Objective: To determine how dual-energy X-ray absorptiometry (DXA) compares to computed tomography (CT) for measuring changes in total thigh skeletal muscle (SM) mass with strength training (ST) in older adults., Subjects: Fifty previously sedentary, relatively healthy older men (n=23, 60 (s.d.=7.5) years) and women (n=27, 60 (s.d.=9.3) years)., Results: Results indicate that there was a significant increase in thigh SM mass with ST measured by both CT (3.9+/-0.4%) and DXA (2.9+/-0.6%) methods (both P<0.001), and there was not a significant difference in percent change between the two methods, although there was a substantial absolute difference ( approximately 2 kg) at baseline between the two methods. Although Bland-Altman plots indicate overall agreement between the percent thigh SM mass changes of DXA vs CT methods, the 3.4% error associated with DXA was greater than the thigh SM mass change from DXA. However, the CT measured change in thigh SM mass was greater than its error (0.6%)., Conclusions: DXA overestimates baseline and after ST thigh SM mass, and may not be able to detect small changes in thigh SM mass with ST due to its higher error. Although DXA has certain advantages that warrant is used in epidemiologic and intervention studies, improvements to DXA are needed for the accurate assessment of small changes in thigh SM mass.

To examine the influence of insulin-like growth factor (IGF) pathway gene polymorphisms on muscle mass and strength responses to strength training (ST), we studied 128 White and Black men and women before and after a 10-wk single-leg knee extension ST program. One-repetition maximum strength, muscle volume (MV) via computed tomography, and muscle quality (MQ) were assessed at baseline and after 10 wk of ST. There was a significant combined IGF1 cytosine adenine (CA) repeat gene effect, which included both the IGF1 CA repeat main effect and IGF1 CA repeat x PPP3R1 insertion-deletion (I/D) gene x gene interaction effect, on the changes in strength (P < 0.01) and MQ (P < 0.05) with ST. There was a trend for a significant gene x gene interaction between IGF1 CA repeat and PPP3R1 I/D for changes in strength (P = 0.07) and MQ (P = 0.06) with ST. The influence of the PPP3R1 A-202C gene polymorphism on change in MV with ST approached significance (P = 0.06). The IGF1 CA repeat polymorphism had a significant influence on the change in strength and MV combined with ST (P < 0.05), whereas the influence of the PPP3R1 I/D polymorphism approached significance (P = 0.08). There were no associations between the IGFBP3 A-202C gene polymorphism and the muscle phenotypic responses to ST. These data suggest that two of the three IGF pathway gene polymorphisms identified in this study influence muscle phenotypic responses to ST in both black and white older men and women.

Resistance training using lengthening (eccentric) contractions induces greater increases in muscle size than shortening (concentric) contractions, but the underlying molecular mechanisms are not clear. Using temporal expression profiling, we compared changes in gene expression within 24 h of an acute bout of each type of contractions conducted simultaneously in the quadriceps of different legs. Five healthy young men performed shortening contractions with one leg while the contralateral leg performed lengthening contractions. Biopsies were taken from both legs before exercise and 3, 6, and 24 h afterwards, in the fed state. Expression profiling (n = 3) was performed using a custom-made Affymetrix MuscleChip containing probe sets of approximately 3,300 known genes and expressed sequence tags expressed in skeletal muscle. We identified 51 transcripts differentially regulated between the two exercise modes. Using unsupervised hierarchical clustering, we identified four distinct clusters, three of which corresponded to unique functional categories (protein synthesis, stress response/early growth, and sarcolemmal structure). Using quantitative RT-PCR (n = 5), we verified expression changes (lengthening/shortening) in SIX1 (3 h, -1.9-fold, P < 0.001), CSRP3 (6 h, 2.9-fold, P < 0.05), and MUSTN1 (24 h, 4.3-fold, P < 0.05). We examined whether FBXO32/atrogin-1/MAFbx, a known regulator of protein breakdown and of muscle atrophy was differentially expressed: the gene was downregulated after lengthening contractions (3 h, 2.7-fold, P < 0.05; 6 h, 3.3-fold, P < 0.05; 24 h, 2.3-fold, P < 0.05). The results suggested that lengthening and shortening contractions activated distinct molecular pathways as early as 3 h postexercise. The molecular differences might contribute to mechanisms underlying the physiological adaptations seen with training using the two modes of exercise.

Background: The alpha-actinin-3 (ACTN3) R577X polymorphism has been associated with muscle power performance in cross-sectional studies., Methods: We examined baseline knee extensor concentric peak power (PP) and PP change with approximately 10 weeks of unilateral knee extensor strength training (ST) using air-powered resistance machines in 71 older men (65 [standard deviation = 8] years) and 86 older women (64 [standard deviation = 9] years)., Results: At baseline in women, the XX genotype group had an absolute (same resistance) PP that was higher than the RR (p =.005) and RX genotype groups (p =.02). The women XX group also had a relative (70% of one-repetition maximum [1-RM]) PP that was higher than that in the RR (p =.002) and RX groups (p =.008). No differences in baseline absolute or relative PP were observed between ACTN3 genotype groups in men. In men, absolute PP change with ST in the RR (n = 16) group approached a significantly higher value than in the XX group (n = 9; p =.07). In women, relative PP change with ST in the RR group (n = 16) was higher than in the XX group (n = 17; p =.02)., Conclusions: The results indicate that the ACTN3 R577X polymorphism influences the response of quadriceps muscle power to ST in older adults.

To determine sex and race differences in muscle power per unit of muscle contraction, knee-extensor muscle power normalized for knee-extensor muscle volume was measured in 79 middle-aged and older adults (30 men and 49 women, age range 50-85 years). Results revealed that women displayed a 38% faster peak movement velocity than men and African Americans had a 14% lower peak movement velocity than Whites of a similar age when expressed per unit of involved muscle (p < .001). As expected, men exhibited greater knee-extensor strength and peak power per unit of muscle than women, but women had a faster knee- extension movement velocity per unit of muscle than men at the same relative strength level. Moreover, African Americans had greater knee-extensor muscle volume than Whites but exhibited lower knee-extensor strength and lower movement velocity per unit of muscle when tested at the same relative strength levels.

Peripheral vasculature resistance can play an important role in affecting blood pressure and the development of cardiovascular disease. A better understanding of the genes that encode vasodilators, such as adenosine, will provide insight into the mechanisms underlying cardiovascular disease. We tested whether the adenosine monophosphate deaminase-1 (AMPD1) C34T gene polymorphism was associated with the vasodilatory response to ischemia in Caucasian females aged 18-35 years. Blood samples (n = 58) were analyzed for the C34T variant and resulted in the following genotype groups: CC (n = 45) and CT (n = 13). Mean blood pressure (MBP), heart rate, and forearm blood flow (FBF) measured by venous occlusion plethysmography were measured at baseline and at 1 (peak FBF), 2 and 3 min of vasodilation during reactive hyperemia following 5 min of arm ischemia. To control for interindividual variability in baseline FBF and forearm vascular resistance (FVR) the percent change in FBF and FVR were calculated for each min. The percent decrease in FVR was significantly greater in the CT compared to the CC genotype group (-40+/-4% vs. -24+/-3%, P = 0.01) during the 2nd min of reactive hyperemia. The percent increase in FBF tended to be greater in the CT compared to the CC genotype group (+69+/-9% vs. +42+/-9%, P = 0.07) during the 2nd min of reactive hyperemia after adjustment for percent body fat. Consistent with previous findings of increased production of adenosine during exercise in individuals carrying a T allele, our findings suggest that the AMPD1 C34T polymorphism is associated with vasodilatory response to ischemia in the peripheral vasculature because individuals with the T allele had a greater vasodilatory response to ischemia.

The effects of a 10-wk unilateral knee extension strength training (ST) program on peak power (PP) and peak movement velocity (PV), at given absolute (force load) and relative (same % of 1 repetition maximum) resistances (loads), were examined in 30 older men [64 yr (7 SD)] and 32 older women [62 yr (6 SD)]. PP increased significantly in both men and women at the same absolute (P < 0.001) and relative loads (P < 0.01) with ST. Men had a significantly greater increase in relative PP than women with ST at 60% (P < 0.01) and 70% (P < 0.001) of 1 repetition maximum when covarying for baseline differences and age. However, when each subject was tested at the same absolute load and when PP was normalized for the muscle volume of the trained knee extensors (i.e., absolute muscle power quality), women increased by 9% (P < 0.05), whereas men did not change. Both men and women increased their absolute PV (P < 0.001) but decreased their relative PV significantly with ST (P < 0.05). However, when baseline values and age were covaried, women had significantly less of a decrease in relative PV quality with ST than men (P < 0.01), although the difference was small. These normalized data suggest that ST-induced increases in PP depend on muscular hypertrophy in men, but not in women, providing further support for the hypothesis developed from our previous report (Ivey FM, Tracy BL, Lemmer JT, NessAiver M, Metter EJ, Fozard JL and Hurley BF. J Gerontol A Biol Sci Med Sci 55: B152-B157, 2000) that improvements in muscle function with ST result from nonmuscle mass adaptations to a greater extent in women than men.

The ACE I/D polymorphism has been shown to interact with habitual physical activity levels in postmenopausal women to associate with submaximal and with maximal exercise hemodynamics. This investigation was designed to assess the potential relationships between ACE genotype and oxygen consumption (VO2), cardiac output (Q), stroke volume (SV), heart rate (HR), blood pressure (BP), total peripheral resistance (TPR), and arteriovenous oxygen difference ([a-v]O2 diff) during submaximal and maximal exercise in young sedentary and endurance-trained women. Seventy-seven 18-35-yr-old women underwent a maximal exercise test and a number of cardiac output tests on a treadmill using the acetylene rebreathing technique. ACE genotype was not significantly associated with VO2max (II 41.4+/-1.2, ID 39.8+/-0.9, DD 39.8+/-1.1 ml/kg/min, p=ns) or maximal HR (II 191+/-2, ID 191+/-1, DD 193+/-2 bpm, p=ns). In addition, systolic and diastolic BP, (a-v)O2 diff, TPR, SV, and Q during maximal exercise were not significantly associated with ACE genotype. During submaximal exercise, SBP, Q, SV, HR, TPR, and (a-v)O2 diff were not significantly associated with ACE genotype. However, the association between diastolic BP during submaximal exercise and ACE genotype approached significance (p=0.08). In addition, there were no statistically significant interactions between ACE genotype and habitual physical activity (PA) levels for any of the submaximal or the maximal exercise hemodynamic variables. We conclude that the ACE I/D polymorphism was not associated, independently or interacting with habitual PA levels, submaximal, or maximal cardiovascular hemodynamics in young women.

To determine the influence of the vitamin D receptor (VDR) gene FokI and BsmI genotype on bone mineral density response to two exercise training modalities, 206 healthy men and women (50-81 years old) were studied before and after approximately 5-6 months of either aerobic exercise training (AT) or strength training (ST). A totla of 123 subjects completed AT (51 men, 72 women) and 83 subjects completed ST (40 men, 43 women). DNA was extracted from blood samples of all subjects and genotyping was performed at the VDR FokI and BsmI locus to determine its association to training response. Total body, greater trochanter and femoral neck bone mineral density (BMD) were measured before and after both training programmes using dual-energy X-ray absorptiometry. VDR BsmI genotype was not significantly related to BMD at baseline or after ST or AT. However, VDR FokI genotype was significantly related to ST- but not AT-induced changes in femoral neck BMD (P < 0.05). The heterozygotes (Ff) in the ST group approached a significantly greater increase in femoral neck BMD (P = 0.058) compared to f homozygotes. There were no significant genotype relationships in the AT group. These data indicate that VDR FokI genotype may influence femoral neck BMD response to ST, but not AT.

Strength training (ST) is considered an intervention of choice for the prevention and treatment of sarcopenia. Reports in the literature have suggested that the insulin-like growth factor I protein (IGF-I) plays a major role in ST-induced skeletal muscle hypertrophy and strength improvements. A microsatellite repeat in the promoter region of the IGF1 gene has been associated with IGF-I blood levels and phenotypes related to IGF-I in adult men and women. To examine the influence of this polymorphism on muscle hypertrophic and strength responses to ST, we studied 67 Caucasian men and women before and after a 10-wk single-leg knee-extension ST program. One repetition maximum strength, muscle volume via computed tomography, and muscle quality were assessed at baseline and after 10 wk of training. The IGF1 repeat promoter polymorphism and three single-nucleotide polymorphisms were genotyped. For the promoter polymorphism, subjects were grouped as homozygous for the 192 allele, heterozygous, or noncarriers of the 192 allele. After 10 wk of training, 1-repetition maximum, muscle volume, and muscle quality increased significantly for all groups combined (P < 0.001). However, carriers of the 192 allele gained significantly more strength with ST than noncarriers of the 192 allele (P = 0.02). There was also a nonsignificant trend for a greater increase in muscle volume in 192 carriers than noncarriers (P = 0.08). No significant associations were observed for the other polymorphisms studied. Thus these data suggest that the IGF1 promoter polymorphism may influence the strength response to ST. Larger sample sizes should be used in future studies to verify these results.

Objectives: To examine the possible influences of age and gender on muscle volume responses to strength training (ST)., Design: Prospective intervention study., Setting: University of Maryland Exercise Science and Wellness Research Laboratories., Participants: Eight young men (age 20-30 years), six young women (age 20-30 years), nine older men (age 65-75 years), and ten older women (age 65-75 years)., Intervention: A 6-month whole-body ST program that exercised all major muscle groups of the upper and lower body 3 days/week., Measurements: Thigh and quadriceps muscle volumes and mid-thigh muscle cross-sectional area (CSA) were assessed by magnetic resonance imaging before and after the ST program., Results: Thigh and quadriceps muscle volume increased significantly in all age and gender groups as a result of ST (P < .001), with no significant differences between the groups. Modest correlations were observed between both the change in quadriceps versus the change in total thigh muscle volume (r = 0.65; P < .001) and the change in thigh muscle volume versus the change in mid-thigh CSA (r = 0.76, P < .001)., Conclusions: The results indicate that neither age nor gender affects muscle volume response to whole-body ST. Muscle volume, rather than muscle CSA, is recommended for studying muscle mass responses to ST.