Muscle strength, quantity and quality and muscle fat quantity and their association with oxidative stress in patients with facioscapulohumeral muscular dystrophy: Effect of antioxidant supplementation.

The purpose of this study was to identify causes of quadriceps muscle weakness in facioscapulohumeral muscular dystrophy (FSHD). To this aim, we evaluated quadriceps muscle and fat volumes by magnetic resonance imaging and their relationships with muscle strength and oxidative stress markers in adult patients with FSHD (n = 32) and healthy controls (n = 7), and the effect of antioxidant supplementation in 20 of the 32 patients with FSHD (n = 10 supplementation and n = 10 placebo) (NCT01596803). Compared with healthy controls, the dominant quadriceps strength and quality (muscle strength per unit of muscle volume) were decreased in patients with FSHD. In addition, fat volume was increased, without changes in total muscle volume. Moreover, in patients with FSHD, the lower strength of the non-dominant quadriceps was associated with lower muscle quality compared with the dominant muscle. Antioxidant supplementation significantly changed muscle and fat volumes in the non-dominant quadriceps, and muscle quality in the dominant quadriceps. This was associated with improved muscle strength (both quadriceps) and antioxidant response. These findings suggest that quadriceps muscle strength decline may not be simply explained by atrophy and may be influenced also by the muscle intrinsic characteristics. As FSHD is associated with increased oxidative stress, supplementation might reduce oxidative stress and increase antioxidant defenses, promoting changes in muscle function.

Levothyroxine use and longitudinal changes in thigh muscles in at-risk participants for knee osteoarthritis: preliminary analysis from Osteoarthritis Initiative cohort.

BACKGROUND: We examined the association between levothyroxine use and longitudinal MRI biomarkers for thigh muscle mass and composition in at-risk participants for knee osteoarthritis (KOA) and their mediatory role in subsequent KOA incidence. METHODS: Using the Osteoarthritis Initiative (OAI) data, we included the thighs and corresponding knees of participants at risk but without established radiographic KOA (baseline Kellgren-Lawrence grade (KL) < 2). Levothyroxine users were defined as self-reported use at all annual follow-up visits until the 4th year and were matched with levothyroxine non-users for potential confounders (KOA risk factors, comorbidities, and relevant medications covariates) using 1:2/3 propensity score (PS) matching. Using a previously developed and validated deep learning method for thigh segmentation, we assessed the association between levothyroxine use and 4-year longitudinal changes in muscle mass, including cross-sectional area (CSA) and muscle composition biomarkers including intra-MAT (within-muscle fat), contractile percentage (non-fat muscle CSA/total muscle CSA), and specific force (force per CSA). We further assessed whether levothyroxine use is associated with an 8-year risk of standard KOA radiographic (KL ≥ 2) and symptomatic incidence (incidence of radiographic KOA and pain on most of the days in the past 12 months). Finally, using a mediation analysis, we assessed whether the association between levothyroxine use and KOA incidence is mediated via muscle changes. RESULTS: We included 1043 matched thighs/knees (266:777 levothyroxine users:non-users; average ± SD age: 61 ± 9 years, female/male: 4). Levothyroxine use was associated with decreased quadriceps CSAs (mean difference, 95%CI: - 16.06 mm2/year, - 26.70 to - 5.41) but not thigh muscles' composition (e.g., intra-MAT). Levothyroxine use was also associated with an increased 8-year risk of radiographic (hazard ratio (HR), 95%CI: 1.78, 1.15-2.75) and symptomatic KOA incidence (HR, 95%CI: 1.93, 1.19-3.13). Mediation analysis showed that a decrease in quadriceps mass (i.e., CSA) partially mediated the increased risk of KOA incidence associated with levothyroxine use. CONCLUSIONS: Our exploratory analyses suggest that levothyroxine use may be associated with loss of quadriceps muscle mass, which may also partially mediate the increased risk of subsequent KOA incidence. Study interpretation should consider underlying thyroid function as a potential confounder or effect modifier. Therefore, future studies are warranted to investigate the underlying thyroid function biomarkers for longitudinal changes in the thigh muscles.

A randomized controlled trial to determine whether beta-hydroxy-beta-methylbutyrate and/or eicosapentaenoic acid improves diaphragm and quadriceps strength in critically Ill mechanically ventilated patients.

BACKGROUND: Intensive care unit acquired weakness is a serious problem, contributing to respiratory failure and reductions in ambulation. Currently, there is no pharmacological therapy for this condition. Studies indicate, however, that both beta-hydroxy-beta-methylbutyrate (HMB) and eicosapentaenoic acid (EPA) increase muscle function in patients with cancer and in older adults. The purpose of this study was to determine whether HMB and/or EPA administration would increase diaphragm and quadriceps strength in mechanically ventilated patients. METHODS: Studies were performed on 83 mechanically ventilated patients who were recruited from the Medical Intensive Care Units at the University of Kentucky. Diaphragm strength was assessed as the trans-diaphragmatic pressure generated by supramaximal magnetic phrenic nerve stimulation (PdiTw). Quadriceps strength was assessed as leg force generated by supramaximal magnetic femoral nerve stimulation (QuadTw). Diaphragm and quadriceps thickness were assessed by ultrasound. Baseline measurements of muscle strength and size were performed, and patients were then randomized to one of four treatment groups (placebo, HMB 3 gm/day, EPA 2 gm/day and HMB plus EPA). Strength and size measurements were repeated 11 days after study entry. ANCOVA statistical testing was used to compare variables across the four experimental groups. RESULTS: Treatments failed to increase the strength and thickness of either the diaphragm or quadriceps when compared to placebo. In addition, treatments also failed to decrease the duration of mechanical ventilation after study entry. CONCLUSIONS: These results indicate that a 10-day course of HMB and/or EPA does not improve skeletal muscle strength in critically ill mechanically ventilated patients. These findings also confirm previous reports that diaphragm and leg strength in these patients are profoundly low. Additional studies will be needed to examine the effects of other anabolic agents and innovative forms of physical therapy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01270516. Registered 5 January 2011, https://clinicaltrials.gov/ct2/show/NCT01270516?term=Supinski&draw=2&rank=4 .

Effects of ß-hydroxy-ß-methylbutyrate supplementation on muscle mass and strength in onabotulinumtoxin type-A-injected and contralateral quadriceps femoris in rabbits.

OBJECTIVE: To determine the effects of the leucine metabolite ß-hydroxy-ß-methylbutyrate (HMB) on strength, muscle mass, and contractile material in muscle wasting induced by onabotulinumtoxin type-A (BoNT-A) injection into the quadriceps femoris muscles of New Zealand white rabbits. METHODS: A total of 21, female rabbits were divided into 3 groups (n=7, each). Group 1 (Control) received intramuscular injection of saline. Groups 2 and 3 received intramuscular injection of BoNT-A (3.5 units/kg), with group 3 receiving supplementation with HMB (120 mg/kg-BW/day). Muscle morphology, mass, and strength were assessed 8 weeks later in both injected and non-injected contralateral limbs. RESULTS: Injected muscle strength of group 2 (BoNT-A) and group 3 (BoNT-A+HMB) was reduced by 63% and 60%, respectively, compared with Controls (p<0.0001). Strength in contralateral muscles of group 2 was reduced by 23% vs Controls (p<0.002), while in group 3, strength was similar to Controls. Muscle mass in the injected muscles of the BoNT-A and BoNT-A+HMB groups was significantly reduced, by 46% and 48%, respectively. CONCLUSION: While HMB did not prevent loss of muscle strength and mass in the BoNT-A-injected musculature, it prevented significant loss of contractile material in the injected musculature and strength loss in the contralateral non-injected musculature.

Sarcopenia, oxidative stress and inflammatory process in muscle of cirrhotic rats - Action of melatonin and physical exercise.

Sarcopenia is one of the most common features of cirrhosis, contributing to morbidity and mortality in this population. We aimed to evaluate the effect of melatonin (MLT) and exercise (EX) on the quadriceps muscle in rats with biliary cirrhosis induced by bile duct ligation (BDL). We used 48 males (mean weight = 300 g), divided into eight groups. A 20 mg/Kg MLT dose was administered via i.p. (1 x daily), and the EX, the animals were set to swim in couples for 10 min each day. Upon completion, blood, liver, and quadriceps samples were taken for analysis. In the liver enzymes analysis and comet assay results, a reduction was observed in the groups treated with MLT with/or EX comparing to the BDL group. In the evaluation of substances that react to thiobarbituric acid (TBARS), nitric oxide levels (NO), and tumor necrosis factor-alpha levels (TNF-α), there was a significant increase in the BDL group and a reduction in the treated groups. In the activity of the superoxide dismutase enzyme (SOD) and interleukin-10 levels (IL-10) concentrations, there was a significant increase in the treated groups of the BDL group. Histological analysis revealed muscle hypotrophy in the BDL group in comparison with the control group (CO) and increased muscle mass in the treated groups. There was an increase in weight gain and phase angle in the groups treated with MLT with/or EX comparing to the BDL group. We suggest that treatments may contribute to the reduction of muscle changes in cirrhotic patients.

Effect of oral isotretinoin on muscle strength in patients with acne vulgaris: a prospective controlled study.

BACKGROUND: Musculoskeletal side effects related to isotretinoin are frequently reported. This study aimed to investigate the effect of oral isotretinoin treatment on muscle strength. Our second aim was to evaluate whether there was a correlation between the serum creatine phosphokinase (CPK) level, a specific marker of muscle breakdown, and muscle strength. METHODS: This study included 30 patients who presented to our hospital and were started on oral isotretinoin treatment for acne vulgaris and 30 patients in the control group who were given local treatment. Age, sex, height and weight of the patients were recorded, and the body mass index (BMI) was calculated. The hamstring and quadriceps muscle strengths of the non-dominant side were evaluated in all patients using an isokinetic dynamometer, and the peak torque (PT) values ​​were recorded. In the isotretinoin group, isokinetic measurements were performed again in those that completed six-month drug treatment and compared with the initial PT values. RESULTS: The two groups were similar in terms of age, sex, and BMI (p > 0.05). There was no significant difference between the isotretinoin and control groups in terms of muscle strength at the beginning of the treatment (p > 0.05). No significant change was observed in hamstring and quadriceps PT values in the isotretinoin group after 6 months of treatment compared to baseline (p > 0.05). No statistically significant correlation was found between the serum CPK level and hamstring and quadriceps muscle strength (p > 0.05). CONCLUSION: Oral isotretinoin doesn't alter muscle strength. There is no relationship between the serum CPK levels and muscle strength.

Influence of low-dose aspirin, resistance exercise, and sex on human skeletal muscle PGE2 /COX pathway activity.

Prostaglandin (PG) E2  has been linked to increased inflammation and attenuated resistance exercise adaptations in skeletal muscle. Nonaspirin cyclooxygenase (COX) inhibitors have been shown to reduce these effects. This study examined the effect of low-dose aspirin on skeletal muscle COX production of PGE2 at rest and following resistance exercise. Skeletal muscle (vastus lateralis) biopsies were taken from six individuals (4 M/2 W) before and 3.5 hr after a single bout of resistance exercise for ex vivo PGE2 production under control and low (10 µM)- or standard (100 µM)-dose aspirin conditions. Sex-specific effects of aspirin were also examined by combining the current findings with our previous similar ex vivo skeletal muscle investigations (n = 20, 10 M/10 W). Low-dose aspirin inhibited skeletal muscle PGE2 production (p < 0.05). This inhibition was similar to standard-dose aspirin (p > 0.05) and was not influenced by resistance exercise (p > 0.05) (overall effect: -18 ± 5%). Men and women had similar uninhibited skeletal muscle PGE2 production at rest (men: 1.97 ± 0.33, women: 1.96 ± 0.29 pg/mg wet weight/min; p > 0.05). However, skeletal muscle of men was 60% more sensitive to aspirin inhibition than women (p < 0.05). In summary, the current findings 1) confirm low-dose aspirin inhibits the PGE2 /COX pathway in human skeletal muscle, 2) show that resistance exercise does not alter aspirin inhibitory efficacy, and 3) suggest the skeletal muscle of men and women could respond differently to long-term consumption of low-dose aspirin, one of the most common chronically consumed drugs in the world.

Heterogeneity in insulin-stimulated glucose uptake among different muscle groups in healthy lean people and people with obesity.

AIMS/HYPOTHESIS: It has been proposed that muscle fibre type composition and perfusion are key determinants of insulin-stimulated muscle glucose uptake, and alterations in muscle fibre type composition and perfusion contribute to muscle, and consequently whole-body, insulin resistance in people with obesity. The goal of the study was to evaluate the relationships among muscle fibre type composition, perfusion and insulin-stimulated glucose uptake rates in healthy, lean people and people with obesity. METHODS: We measured insulin-stimulated whole-body glucose disposal and glucose uptake and perfusion rates in five major muscle groups (erector spinae, obliques, rectus abdominis, hamstrings, quadriceps) in 15 healthy lean people and 37 people with obesity by using the hyperinsulinaemic-euglycaemic clamp procedure in conjunction with [2H]glucose tracer infusion (to assess whole-body glucose disposal) and positron emission tomography after injections of [15O]H2O (to assess muscle perfusion) and [18F]fluorodeoxyglucose (to assess muscle glucose uptake). A biopsy from the vastus lateralis was obtained to assess fibre type composition. RESULTS: We found: (1) a twofold difference in glucose uptake rates among muscles in both the lean and obese groups (rectus abdominis: 67 [51, 78] and 32 [21, 55] µmol kg-1 min-1 in the lean and obese groups, respectively; erector spinae: 134 [103, 160] and 66 [24, 129] µmol kg-1 min-1, respectively; median [IQR]) that was unrelated to perfusion or fibre type composition (assessed in the vastus only); (2) the impairment in insulin action in the obese compared with the lean group was not different among muscle groups; and (3) insulin-stimulated whole-body glucose disposal expressed per kg fat-free mass was linearly related with muscle glucose uptake rate (r2 = 0.65, p < 0.05). CONCLUSIONS/INTERPRETATION: Obesity-associated insulin resistance is generalised across all major muscles, and is not caused by alterations in muscle fibre type composition or perfusion. In addition, insulin-stimulated whole-body glucose disposal relative to fat-free mass provides a reliable index of muscle glucose uptake rate.

Resveratrol-induced remodelling of myocellular lipid stores: A study in metabolically compromised humans.

In non-athletes, insulin sensitivity correlates negatively with intramyocellular lipid (IMCL) content. In athletes, however, a pattern of benign IMCL storage exists, which is characterized by lipid storage in type I muscle fibres, in small and numerous lipid droplets (LDs) preferable coated with PLIN5, without affecting insulin sensitivity. Administration of resveratrol has been promoted for its beneficial effects on glucose homeostasis. We observed that 30 days of oral resveratrol administration (150 mg/day) in metabolically compromised individuals showed a 33% increase in IMCL (placebo vs. resveratrol; 0.86 ± 0.090 AU vs. 1.14 ± 0.11 AU, p = 0.003) without impeding insulin sensitivity. Thus, the aim of the present study was to examine if a resveratrol-mediated increase in IMCL content, in metabolically compromised individuals, changes the LD phenotype towards the phenotype we previously observed in athletes. For this, we studied IMCL, LD number, LD size, subcellular distribution and PLIN5 coating in different fibre types using high-resolution confocal microscopy. As proof of concept, we observed a 2.3-fold increase (p = 0.038) in lipid accumulation after 48 h of resveratrol incubation in cultured human primary muscle cells. In vivo analysis showed that resveratrol-induced increase in IMCL is predominantly in type I muscle fibres (placebo vs. resveratrol; 0.97 ± 0.16% vs. 1.26 ± 0.09%; p = 0.030) in both the subsarcolemmal (p = 0.016) and intermyofibrillar region (p = 0.026) and particularly in PLIN5-coated LDs (p = 0.024). These data indicate that administration of resveratrol augments IMCL content in metabolically compromised individuals towards a LD phenotype that mimics an 'athlete like phenotype'.

Quadriceps Weakness After Single-Shot Adductor Canal Block: A Multivariate Analysis of 1,083 Primary Total Knee Arthroplasties.

BACKGROUND: Adductor canal blocks (ACBs) are commonly employed in multimodal pain control for total knee arthroplasty (TKA) and minimize motor blockade compared with femoral nerve blocks. Quadriceps weakness may be associated with ACBs. The purpose of this study was to quantify the prevalence of clinically relevant quadriceps weakness after a single-shot ACB and to identify the factors that are associated with its diagnosis. METHODS: The study group consisted of 1,083 retrospectively reviewed consecutive TKAs that were performed with ACBs at an academic hip and knee center. Quadriceps weakness was quantified with a standardized rating system during the initial physical therapy evaluation, and 23 potential covariates were analyzed. RESULTS: The prevalence of quadriceps weakness was 9%. Increasing the dose of the ACB anesthetic per unit of body mass index (BMI) increased the probability of quadriceps weakness by 5.0 times (95% confidence interval [CI], 1.9 to 13.3; p = 0.001). The highest probability of quadriceps weakness (52.9%) was associated with women who received the highest anesthetic dose per unit of BMI and an epinephrine extender but no corticosteroid extender. CONCLUSIONS: The optimal volume of local anesthetic in ACBs to maintain pain control while minimizing quadriceps weakness has not yet been defined. Our observation that quadriceps weakness was associated with increasing doses of ACB anesthetic per unit of BMI suggests that more than traditional structural canal-fill parameters (i.e., filling the distal aspect of the adductor canal without spreading to the femoral triangle) should be considered when choosing injectates and injectate volumes for ACBs. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Comparison between subarachnoid morphine and femoral nerve block for analgesia after knee ligament reconstruction: a randomized clinical trial / Comparação entre morfina subaracnoidea e bloqueio do nervo femoral para analgesia após reconstrução ligamentar de joelho: estudo clínico randomizado

Abstract Background and objectives There are no consensus of the ideal technique to provide analgesia in knee ligament reconstructions. The aim of this study was to compare the intensity of postoperative pain in these patients under different modalities of analgesia. Method Randomized and controlled clinical trial of patients undergoing reconstruction of the Anterior Cruciate Ligament (ACL) with flexor tendons between December 2013 and 2014. All patients underwent spinal anesthesia and rescue analgesia with tramadol. The groups C, M, R0,375 and R0,25 was compared with only the previously described technique, subarachnoid morphine (100░µg), or Femoral Nerve Block (BNF) with 25░mL of 0.375% ropivacaine and 0.25%, respectively. Pain intensity at 6, 12 and 24░hours, age, sex, rescue analgesia, adverse reactions and satisfaction were evaluated. Results Among the 83 eligible patients, a predominance of males (85.7%) was observed, between 28 and 31 years. The group C requested more opioid (27.3%) than the other groups, without significance when compared. There were no significant differences in pain intensity at 6, 12 and 24░hours. There was a higher incidence of urinary retention in the M group (23.8%) than in the R0,375 (0%) and prolonged quadriceps motor block in the R0,375 group (30%) than in the M and C groups (0%), with statistical significance (p░<░0.05). Conclusion There was no difference in the intensity of postoperative pain in patients submitted to ACL reconstruction with flexor tendons under the analgesic modalities evaluated, despite the predominance of urinary retention in the M group and motor block in the R0,375 group.

Resumo Justificativa e objetivos Não há consenso sobre qual é a técnica ideal para prover analgesia em reconstruções ligamentares de joelho. Objetivou‐se comparar a intensidade da dor pós‐operatória desses pacientes sob diferentes modalidades de analgesia. Método Ensaio clínico randomizado e controlado de pacientes submetidos à reconstrução do ligamento cruzado anterior com tendões flexores entre dezembro de 2013 e 2014. Todos os pacientes foram submetidos a raquianestesia e analgesia de resgate com tramadol. Compararam‐se os grupos C, M, R0,375 e R0,25; aos quais se ofertou apenas a técnica anteriormente descrita, morfina subaracnóidea (100 µg) ou bloqueio de nervo femoral com 25 mL de ropivacaína 0,375% e 0,25%, respectivamente. Avaliou‐se intensidade da dor em 6, 12 e 24 horas, idade, sexo, analgesia de resgate, reações adversas e satisfação. Resultados Entre os 83 pacientes elegíveis, observou‐se predomínio do sexo masculino (85,7%) entre 28 e 31 anos. O Grupo C solicitou mais opioide (27,3%) do que os demais grupos, sem significância quando comparados. Não houve diferenças significativas na intensidade da dor em 6, 12 e 24 horas. Houve maior incidência de retenção urinária no Grupo M (23,8%) do que no R0,375 (0%) e de bloqueio motor prolongado do quadríceps no Grupo R0,375 (30%) do que nos Grupos M e C (0%), com significância estatística (p< 0,05). Conclusão Não houve diferença na intensidade da dor pós‐operatória nos pacientes submetidos à reconstrução de ligamento cruzado anterior com tendões flexores sob as modalidades analgésicas avaliadas, apesar do predomínio de retenção urinária no Grupo M e bloqueio motor no Grupo R0,375.

Aerobic exercise induces tumor suppressor p16INK4a expression of endothelial progenitor cells in human skeletal muscle.

Aerobic exercise induces oxidative stress and DNA damage, nevertheless, lowers cancer incidence. It remains unclear how genetic stability is maintained under this condition. Here, we examined the dynamic change of the tumor suppressor p16INK4a in cells of skeletal muscle among young men following 60-min of aerobic cycling at 70% maximal oxygen consumption (V̇O2max). Rg1 (5 mg, an immunostimulant ginsenoside) and placebo (PLA) were supplemented 1 h before exercise. Data from serial muscle biopsies shows unchanged p16INK4a+ cells after exercise followed by a considerable increase (+21-fold) in vastus lateralis muscle 3 h later. This increase was due to the accumulation of endothelial progenitor cells (p16INK4a+/CD34+) surrounding myofibers and other infiltrated nucleated cells (p16INK4a+/CD34-) in necrotic myofibers. During the Rg1 trial, acute increases of p16INK4a+ cells in the muscle occurred immediately after exercise (+3-fold) and reversed near baseline 3 h later. Rg1 also lowered IL-10 mRNA relative to PLA 3 h after exercise. Post-exercise increases in VEGF mRNA and CD163+ macrophages were similar for PLA and Rg1 trials. Conclusion: The marked increases in p16INK4a protein expression of endothelial progenitor cells in skeletal muscle implicates a protective mechanism for maintaining genetic stability against aerobic exercise. Rg1 accelerates resolution of the exercise-induced stress response.

[Comparison between subarachnoid morphine and femoral nerve block for analgesia after knee ligament reconstruction: a randomized clinical trial]. / Comparação entre morfina subaracnoidea e bloqueio do nervo femoral para analgesia após reconstrução ligamentar de joelho: estudo clínico randomizado.

BACKGROUND AND OBJECTIVES: There is no consensus of the ideal technique to provide analgesia in knee ligament reconstructions. The aim of this study was to compare the intensity of postoperative pain in these patients under different modalities of analgesia. METHOD: Randomized and controlled clinical trial of patients undergoing reconstruction of the anterior cruciate ligament (ACL) with flexor tendons between December 2013 and 2014. All patients underwent spinal anesthesia and rescue analgesia with tramadol. The Groups C, M, R0,375 and R0,25 were compared with only the previously described technique, subarachnoid morphine (100 µg) or femoral nerve block with 25 mL of 0.375% ropivacaine and 0.25%, respectively. Pain intensity at 6, 12 and 24hours, age, sex, rescue analgesia, adverse reactions and satisfaction were evaluated. RESULTS: Among the 83 eligible patients, a predominance of males (85.7%) was observed, between 28 and 31 years. The Group C requested more opioid (27.3%) than the other groups, without significance when compared. There were no significant differences in pain intensity at 6, 12 and 24hours. There was a higher incidence of urinary retention in the Group M (23.8%) than in the R0,375 (0%) and prolonged quadriceps motor block in the R0,375 Group (30%) than in the M and C Groups (0%), with statistical significance (p < 0.05). CONCLUSION: There was no difference in the intensity of postoperative pain in patients submitted to anterior cruciate ligament reconstruction with flexor tendons under the analgesic modalities evaluated, despite the predominance of urinary retention in the M Group and motor block in the R0,375 Group.

Metformin alters skeletal muscle transcriptome adaptations to resistance training in older adults.

Evidence from clinical trials and observational studies suggests that both progressive resistance exercise training (PRT) and metformin delay a variety of age-related morbidities. Previously, we completed a clinical trial testing the effects of 14 weeks of PRT + metformin (metPRT) compared to PRT with placebo (plaPRT) on muscle hypertrophy in older adults. We found that metformin blunted PRT-induced muscle hypertrophic response. To understand potential mechanisms underlying the inhibitory effect of metformin on PRT, we analyzed the muscle transcriptome in 23 metPRT and 24 plaPRT participants. PRT significantly increased expression of genes involved in extracellular matrix remodeling pathways, and downregulated RNA processing pathways in both groups, however, metformin attenuated the number of differentially expressed genes within these pathways compared to plaPRT. Pathway analysis showed that genes unique to metPRT modulated aging-relevant pathways, such as cellular senescence and autophagy. Differentially expressed genes from baseline biopsies in older adults compared to resting muscle from young volunteers were reduced following PRT in plaPRT and were further reduced in metPRT. We suggest that although metformin may blunt pathways induced by PRT to promote muscle hypertrophy, adjunctive metformin during PRT may have beneficial effects on aging-associated pathways in muscle from older adults.

Muscle contractile properties of cancer patients receiving chemotherapy: Assessment of feasibility and exercise effects.

BACKGROUND: This pilot trial explores the feasibility of measuring muscle contractile properties in patients with cancer, effects of exercise during chemotherapy on muscle contractile properties and the association between changes in contractile muscle properties and perceived fatigue. METHOD: Patients who received (neo)adjuvant chemotherapy for breast or colon cancer were randomized to a 9-12 week exercise intervention or a waitlist-control group. At baseline and follow-up, we measured knee extensor strength using maximal voluntary contraction (MVC), contractile muscle properties of the quadriceps muscle using electrical stimulation, and perceived fatigue using the Multidimensional Fatigue Inventory. Feasibility was assessed by the proportion of patients who successfully completed measurements of contractile muscle properties. Exercise effects on muscle contractile properties were explored using linear regression analyses. Between-group differences >10% were considered potentially relevant. Pearson correlation (rp ) of changes in contractile muscle properties and changes in perceived fatigue was calculated. RESULTS: Twenty two of 30 patients completed baseline and follow-up assessments. Measurements of contractile properties were feasible except for muscle fatigability. We found a potentially relevant between-group difference in the rate of force development favoring the intervention group (1192 N/s, 95% CI = -335; 2739). Change in rate of force development was negatively correlated with change in perceived general (rp  = -0.54, P = .04) and physical (rp  = -0.59, P = .02) fatigue. CONCLUSION: Chemotherapy induces a decrease in the rate of force development, which may reflect a larger loss in type II muscle fibers. This may be attenuated with (resistance) exercise. The increase in the rate of force development was related to a decrease in perceived fatigue.

Influence of muscle oxygenation and nitrate-rich beetroot juice supplementation on O2 uptake kinetics and exercise tolerance.

We tested the hypothesis that acute supplementation with nitrate (NO3-)-rich beetroot juice (BR) would improve quadriceps muscle oxygenation, pulmonary oxygen uptake (V˙O2) kinetics and exercise tolerance (Tlim) in normoxia and that these improvements would be augmented in hypoxia and attenuated in hyperoxia. In a randomised, double-blind, cross-over study, ten healthy males completed two-step cycle tests to Tlim following acute consumption of 210 mL BR (18.6 mmol NO3-) or NO3--depleted beetroot juice placebo (PL; 0.12 mmol NO3-). These tests were completed in normobaric normoxia [fraction of inspired oxygen (FIO2): 21%], hypoxia (FIO2: 15%) and hyperoxia (FIO2: 40%). Pulmonary V˙O2 and quadriceps tissue oxygenation index (TOI), derived from multi-channel near-infrared spectroscopy, were measured during all trials. Plasma [nitrite] was higher in all BR compared to all PL trials (P < 0.05). Quadriceps TOI was higher in normoxia compared to hypoxia (P < 0.05) and higher in hyperoxia compared to hypoxia and normoxia (P < 0.05). Tlim was improved after BR compared to PL ingestion in the hypoxic trials (250 ± 44 vs. 231 ± 41 s; P = 0.006; d = 1.13), with the magnitude of improvement being negatively correlated with quadriceps TOI at Tlim (r = -0.78; P < 0.05). Tlim was not improved following BR ingestion in normoxia (BR: 364 ± 98 vs. PL: 344 ± 78 s; P = 0.087, d = 0.61) or hyperoxia (BR: 492 ± 212 vs. PL: 472 ± 196 s; P = 0.273, d = 0.37). BR ingestion increased peak V˙O2 in hypoxia (P < 0.05), but not normoxia or hyperoxia (P > 0.05). These findings indicate that BR supplementation is more likely to improve Tlim and peak V˙O2 in situations when skeletal muscle is more hypoxic.

Exploring the Mechanism of Skeletal Muscle in a Tacrolimus-Induced Posttransplantation Diabetes Mellitus Model on Gene Expression Profiles.

OBJECTIVE: Posttransplantation diabetes mellitus (PTDM) is a known complication of transplantation that affects the prognosis. Tacrolimus (Tac or FK506) is a widely used immunosuppressant that has been reported to be a risk factor for PTDM and to further induce complications in heart and skeletal muscles, but the mechanism is still largely unknown. In our preliminary experiments, we found that after Tac treatment, blood glucose increased, and the weight of skeletal muscle declined. Here, we hypothesize that tacrolimus can induce PTDM and influence the atrophy of skeletal muscle. METHODS: We designed preliminary experiments to establish a tacrolimus-induced PTDM model. Gene expression profiles in quadriceps muscle from this rat model were characterized by oligonucleotide microarrays. Then, differences in gene expression profiles in muscle from PTDM rats that received tacrolimus and control subjects were analyzed by using GeneSpring GX 11.0 software (Agilent). Functional annotation and enrichment analysis of differentially expressed genes (DEGs) helped us identify clues for the side effects of tacrolimus. RESULTS: Our experiments found that the quadriceps in tacrolimus-induced PTDM group were smaller than those in the control group. The study identified 275 DEGs that may be responsible for insulin resistance and the progression of PTDM, including 86 upregulated genes and 199 downregulated genes. GO and KEGG functional analysis of the DEGs showed a significant correlation between PTDM and muscle development. PPI network analysis screened eight hub genes and found that they were related to troponin and tropomyosin. CONCLUSIONS: This study explored the molecular mechanism of muscle atrophy in a tacrolimus-induced PTDM model by bioinformatics analyses. We identified 275 DEGs and identified significant biomarkers for predicting the development and progression of tacrolimus-induced PTDM.

Resveratrol and metabolic health in COPD: A proof-of-concept randomized controlled trial.

BACKGROUND: Patients with COPD are often characterized by disturbed metabolic health which is reflected in altered body composition. Current studies in healthy subjects suggest that resveratrol improves metabolic health by enhancing muscle mitochondrial function and adipose tissue morphology. The primary objective was to investigate the effect of four weeks resveratrol supplementation on muscle mitochondrial function in patients with COPD. Secondary objectives were to investigate the effect of resveratrol on adipose tissue inflammatory and metabolic gene expression, systemic inflammation and body composition in patients with COPD. METHODS: In a double-blind randomized placebo-controlled proof-of-concept study, 21 COPD patients (FEV1: 53 ± 15% predicted; age: 67 ± 9 years and BMI: 24.5 ± 3.3 kg/m2) received resveratrol (150 mg/day) or placebo for four weeks. Before and after intervention, blood samples, quadriceps muscle and subcutaneous abdominal fat biopsies were obtained for metabolic and inflammatory profiling. Body composition was assessed by dual energy X-ray absorptiometry. RESULTS: Muscle mitochondrial biogenesis regulators AMPK, SIRT1 and PGC-1α as well as mitochondrial respiration, Oxphos complexes, oxidative enzyme activities and kynurenine aminotransferases were not improved by resveratrol. Plasma high-sensitive C-reactive protein and kynurenine did not change after resveratrol supplementation. Adipose tissue inflammatory markers were unaffected by resveratrol, while markers of glycolysis and lipolysis were significantly increased compared to placebo supplementation. Body weight decreased after resveratrol supplementation (resveratrol -0.95 ± 1.01 kg vs placebo -0.16 ± 0.66 kg, p = 0.049) due to a reduction in lean mass (resveratrol -1.79 ± 1.67 kg vs 0.37 ± 0.86 kg, p = 0.026). CONCLUSION: We do not confirm previously reported positive effects of resveratrol on skeletal muscle mitochondrial function in patients with COPD, but show an unexpected decline in lean mass. CLINICAL TRIAL REGISTRY: Clinicaltrials.gov NCT02245932.

Quadriceps muscle strength in Duchenne muscular dystrophy and effect of corticosteroid treatment.

OBJECTIVES: In Duchenne muscular dystrophy, quadriceps weakness is recognized as a key factor in gait deterioration. The objective of this work was three-fold: first, to document the strength of the quadriceps in corticosteroid-naïve DMD boys; second, to measure the effect of corticosteroids on quadriceps strength; and third, to evaluate the correlation between baseline quadriceps strength and the age when starting corticosteroids with the loss of ambulation. METHODS: Quadriceps muscle strength using hand-held dynamometry was measured in 12 ambulant DMD boys who had never taken corticosteroids and during corticosteroid treatment until the loss of ambulation. RESULTS: Baseline quadriceps muscle strength at 6 years of age was 28% that of normal children of the same age; it decreased to 15% at 8 years and to 6% at 10 years. The increase in quadriceps muscle strength obtained after 1 year of corticosteroid treatment had a strong direct correlation with the baseline strength (R = 0.96). With corticosteroid treatment, the age of ambulation loss showed a very strong direct relationship (R = 0.92) with baseline quadriceps muscle strength but only a very weak inverse relationship (R = -0.73) with the age of starting treatment. Age of loss of ambulation was 10.3 ± 0.5 vs 19.1 ± 4.7 (P < 0.05) in children with baseline quadriceps muscle strength less than or greater than 40 N, respectively. CONCLUSIONS: Corticosteroid-naïve DMD boys have a quantifiable severe progressive quadriceps weakness. This long-term study, for the first time, shows that both of the positive effects obtained with CS treatment, i.e. increasing quadriceps strength and delaying the loss of ambulation, have a strong and direct correlation with baseline quadriceps muscle strength. As such, hand-held dynamometry may be a useful tool in the routine physical examination and during clinical trial assessment.

Cigarette Smoking Is Associated With Lower Quadriceps Cross-sectional Area and Attenuation in Older Adults.

INTRODUCTION: In addition to well-established links with cardiovascular and respiratory diseases, cigarette smoking may affect skeletal muscle; however, associations with quadriceps atrophy, density, and function are unknown. This study explored the associations of current and former smoking with quadriceps muscle area and attenuation as well as muscle force (assessed as knee extension peak torque) and rate of torque development-a measure of muscle power in older adults. METHODS: Data from 4469 older adults, aged 66-95 years at baseline in the Age, Gene/Environment Susceptibility-Reykjavik Study with measurements of thigh computed tomography, isometric knee extension testing, self-reported smoking history, and potential covariates were analyzed. RESULTS: Sex differences were observed in these data; therefore, our final analyses are stratified by sex. In men, both former smokers and current smokers had lower muscle area (with ß= -0.10, 95% confidence interval [CI] = -0.17 to -0.03 and ß = -0.19, 95% CI = -0.33 to -0.05, respectively) and lower muscle attenuation (ie, higher fat infiltration, ß = -0.08, 95% CI = -0.16 to -0.01 and ß = -0.17, 95% CI = -0.34 to -0.01, respectively) when compared with never smokers. Smoking status was not associated with male peak torque or rate of torque development. In women, current smoking was associated with lower muscle attenuation (ß = -0.24, 95% CI = -0.34 to -0.13) compared to never smoking. Among female smokers (current and former), muscle attenuation and peak torque were lower with increasing pack-years. CONCLUSIONS: Results suggest that cigarette smoking is related to multiple muscle properties at older age and that these relationships may be different among men and women. IMPLICATIONS: This article presents novel data, as it examined for the first time the relationship between smoking and computed tomography-derived quadriceps muscle size (cross-sectional area) and attenuation. This study suggests that current cigarette smoking is related to higher muscle fat infiltration, which may have significant health implications for the older population, because of its known association with poor physical function, falls, and hip fractures.