Significant Muscle Hypertrophy Research Articles

Skeletal muscle-specific Bambi deletion induces hypertrophy and oxidative switching coupling with adipocyte thermogenesis against metabolic disorders.

Skeletal muscle plays a significant role in both local and systemic energy metabolism. The current investigation aims to explore the role of the Bambi gene in skeletal muscle, focusing on its implications for muscle hypertrophy and systemic metabolism. We hypothesize that skeletal muscle-specific deletion of Bambi induces muscle hypertrophy, improves metabolic performance, and activates thermogenic adipocytes via the reprogramming of progenitor of iWAT, offering potential therapeutic strategies for metabolic syndromes. Leveraging the Chromatin immunoprecipitation (ChIP)-seq and bioinformatics analysis, Bambi gene is shown to be a direct target of HIF2α, which is further confirmed by ChIP-qPCR and promoter luciferase assay. Skeletal muscle-specific Bambi deletion led to significant muscle hypertrophy and improved metabolic parameters, even under high-fat diet conditions. This deletion induced metabolic reprogramming of stromal vascular fractions (SVFs) into thermogenic adipocytes, contributing to systemic metabolic improvements, potentially through the secretory factor. Notably, mice with skeletal muscle-specific Bambi deletion demonstrate resistance to high-fat diet-induced metabolic disorders, highlighting a potential therapeutic pathway for metabolic syndrome management. Thus, skeletal muscle-specific deletion of Bambi triggers muscle growth, enhances metabolic performance, and activates thermogenic adipocytes. These findings suggest Bambi as a novel therapeutic target for metabolic syndromes, providing new insights into the interaction between muscle hypertrophy and systemic metabolic improvement. The study underscores the potential of manipulating muscle physiology to regulate whole-body metabolism, offering a novel perspective on treating metabolic disorders.

Acute Exposure to Pyridostigmine Bromide Disrupts Cholinergic Myenteric Neuroimmune Function in Mice.

Gulf War Illness (GWI) results from chemical exposure during the Gulf War, with notable impacts on gastrointestinal motility. Due to the limited demographic impacted by this ailment,an in-depth investigation of the GWI has yielded little regarding the underlying pathophysiological mechanisms. Here, the hypothesis that exposure to pyridostigmine bromide (PB) results in severe enteric neuro-inflammation, that cascades to disruptions in colonic motility, is tested. The analyses are performed on male C57BL/6 mice that are treated with physiologically similar doses of PB given to GW veterans. When colonic motility is assessed, GWI colons have significantly reduced forces in response to acetylcholine or electrical field stimulation. GWI is also accompanied by high levels of pro-inflammatory cytokines and chemokines, associated with increased numbers of CD40+ pro-inflammatory macrophages within the myenteric plexus. Enteric neurons responsible for mediating colonic motility reside within the myenteric plexus, and PB exposure reduced their numbers. Significant smooth muscle hypertrophy is also observed due to increased inflammation. Together, the results show that PB exposure caused functional and anatomical dysfunction, promoting impaired motility within the colon. Achieving a greater understanding of the mechanisms of GWI will allow more refinement in therapeutic options that improve veterans' quality of life.

Usefulness of An Anal Sphincter Injury Mouse Model by Means of a Balloon Catheter and a New Method of Evaluating Anal Sphincter Function.

BackgroundThe incidence of fecal incontinence is ~2%, and the associated symptoms significantly impact daily life. New treatment methods including electrical stimulation and regenerative therapy using stem cells for fecal incontinence have been reported. We explored the usefulness of an anal sphincter injury mouse model by means of a balloon catheter and focused on the defecation status of mice as a novel method for evaluating anal function. We examined the utility of the mouse model of anal sphincter injury and the efficacy of electrical stimulation as a treatment modality using this model.MethodsA 10‐mm balloon catheter was used to create an anal sphincter injury model in mice. Sphincter function was evaluated in the noninjured (n = 4), injured (n = 4), noninjured electrical stimulation (n = 4), and injured electrical stimulation (n = 4) groups. Defecation status (defecation frequency in 24 h and fecal weight per stool) and pathological evaluation were used for comparison.ResultsThe defecation frequency increased and the fecal weight per stool decreased significantly in the anal sphincter injury model. Pathological evaluation revealed that anal sphincter tears occurred the day after the injury. Meanwhile, the defecation frequency improved on d 7, and the fecal weight per stool gradually normalized to that of the control group and exhibited significant sphincter muscle hypertrophy in the electrical stimulation group.ConclusionAnal sphincter injury using a balloon catheter in mice allowed us to create a uniform model. The evaluation of defecation status in mice is a useful method for comparatively evaluating anal function.

Effects of German Volume Training on Muscle Strength and Muscle Hypertrophy

Strength training is a kind of practice intended to enhance muscle strength and hypertrophy. To maximize these training adaptations, the appropriate modulation of resistance training variables is needed. Objective: To measure the effect of resistance training on muscle strength and hypertrophy between two groups, group A (05 sets) vs. group B (10 sets) over a period of 14 weeks of training. Methods: The data was collected from gym goers at the University of Lahore, aged between 18-25 years, and had experience of resistance training at a recreational level for one year. Twenty trained athletes were incorporated and purposive sampling was used in this study. The training intervention was conducted over three sessions in a week with one day of transition period for proper recovery from fatigue due to high intensity training. Session one consisted of chest and upper back exercises, session two consisted of leg exercises, and session three contained arms and shoulder exercises. The baseline characteristics of both groups were assessed at the initial stage, including age, height, and total body mass, and after training, the paired-samples t-test was used to assess the mean difference between both groups. Results: The mean difference for paired-samples t-test for anterior thigh muscle thickness of group A was -1.900 while group B had -4.900. Similarly, in strength, the mean difference for paired-samples test for1RM leg press of group A was -39.600 whereas group B had -29.800. The results showed that group A gained significant muscle hypertrophy and strength as compared to group B. Conclusion: It was found that 5 sets on each muscle group in a week with three workout sessions showed better results in order to enhance muscle hypertrophy and strength

Myostatin inhibition promotes fast fibre hypertrophy but causes loss of AMP-activated protein kinase signalling and poor exercise tolerance in a model of limb-girdle muscular dystrophy R1/2A.

Limb-girdle muscular dystrophy R1 (LGMD R1) is caused by mutations in the CAPN3 gene and is characterized by progressive muscle loss, impaired mitochondrial function and reductions in the slow oxidative gene expression programme. Myostatin is a negative regulator of muscle growth, and its inhibition improves the phenotype in several muscle wasting disorders. The effect of genetic and pharmacological inhibition of myostatin signalling on the disease phenotype in a mouse model of LGMD R1 (CAPN3 knockout mouse-C3KO) was studied. Inhibition of myostatin signalling in C3KO muscles resulted in significant muscle hypertrophy; however, there were no improvements in muscle strength and exacerbation of exercise intolerance concomitant with further reduction of muscle oxidative capacity was observed. Inhibition of myostatin signalling is unlikely to be a valid therapeutic strategy for LGMD R1. Limb-girdle muscular dystrophy R1 (LGMD R1) is caused by mutations in the CAPN3 gene and is characterized by progressive muscle loss, impaired mitochondrial function and reductions in the slow oxidative gene expression programme. There are currently no therapies available to patients. We sought to determine if induction of muscle growth, through myostatin inhibition, represents a viable therapeutic strategy for this disease. Myostatin is a negative regulator of muscle growth, and its inhibition improves the phenotype in several muscle wasting disorders. However, the effect of myostatin depends on the genetic and pathophysiological context and may not be efficacious in all contexts. We found that genetic inhibition of myostatin through overexpression of follistatin (an endogenous inhibitor of myostatin) in our LGMD R1 model (C3KO) resulted in 1.5- to 2-fold increase of muscle mass for the majority of limb muscles. However, muscle strength was not improved and exercise intolerance was exacerbated. Pharmacological inhibition of myostatin, using an anti-myostatin antibody, resulted in statistically significant increases in muscle mass; however, functional testing did not reveal changes in muscle strength nor endurance in treated C3KO mice. Histochemical and biochemical evaluation of follistatin overexpressing mice revealed a reduction in the percentage of oxidative fibres and decreased activation of AMP-activated protein kinase signalling in transgenics compared to C3KO muscles. Our data suggest that muscle hypertrophy, induced by myostatin inhibition, leads to loss of oxidative capacity, which further compromises metabolically impaired C3KO muscles and thus is unlikely to be a valid strategy for treatment of LGMD R1.

Resistance training-induced muscle hypertrophy is mediated by TGF-β1-Smad signaling pathway in male Wistar rats.

The TGF-β1-Smad pathway is a well-known negative regulator of muscle growth; however, its potential role in resistance training-induced muscle hypertrophy is not clear. The present study proposed to determine whether and how this pathway may be involved in resistance training-induced muscle hypertrophy. Skeletal muscle samples were collected from the control, trained (RT), control + SB431542 (CITGF ), and trained + SB431542 (RTITGF ) animals following 3, 5, and 8 weeks of resistance training. Inhibition of the TGF-β1-Smad pathway by SB431542 augmented muscle satellite cells activation, upregulated Akt/mTOR/S6K1 pathway, and attenuated FOXO1 and FOXO3a expression in the CITGF group (all p < .01), thereby causing significant muscle hypertrophy in animals from the CITGF . Resistance training significantly decreased muscle TGF-β1 expression and Smad3 (P-Smad3S423/425 ) phosphorylation at COOH-terminal residues, augmented Smad2 (P-Smad2-LS245/250/255 ) and Smad3 (P-Smad3-LSer208 ) phosphorylation levels at linker sites (all p < .01), and led to a muscle hypertrophy which was unaffected by SB431542, suggesting that the TGF-β1-Smad signaling pathway is involved in resistance training-induced muscle hypertrophy. The effects of inhibiting the TGF-β1-Smad signaling pathway were not additive to the resistance training effects on FOXO1 and FOXO3a expression, muscle satellite cells activation, and the Akt/mTOR/S6K1 pathway. Resistance training effect of satellite cell differentiation was independent of the TGF-β1-Smad signaling pathway. These results suggested that the effect of the TGF-β1-Smad signaling pathway on resistance training-induced muscle hypertrophy can be attributed mainly to its diminished inhibitory effects on satellite cell activation and protein synthesis. Suppressed P-Smad3S423/425 and enhanced P-Smad2-LS245/250/255 and P-Smad3-LSer208 are the molecular mechanisms that link the TGF-β1-Smad signaling pathway to resistance training-induced muscle hypertrophy.

Muscle cross-sectional area and motor unit properties of the medial gastrocnemius and vastus lateralis in normal weight and overfat children.

What is the central question of this study? Are differences in muscle size and motor unit properties between normal weight and overfat children muscle specific? What is the main finding and its importance? Muscle cross-sectional area and motor unit action potential amplitudes and firing rates were similar between overfat and normal weight children for both the medial gastrocnemius and vastus lateralis muscles. There was no evidence that the chronic mechanical overload provided by the greater body mass resulted in significant hypertrophy of contractile tissue or motor units that would be used during lower-to-moderate intensity activities. This study examined the possible differences in muscle cross-sectional area (mCSA), motor unit action potential amplitudes (MUAPAMPS ) and interspike intervals (ISIs) of the firing instances of the medial gastrocnemius (MG) and vastus lateralis (VL) between normal weight (NW) and overfat (OF) children aged 7-10years. Fourteen NW (age=8.6±1.1years, BMI=15.8±1.4kgm-2 ) and 12 OF (age=8.8±0.9years, BMI=21.8±2.4kgm-2 ) children performed isometric trapezoidal muscle actions at 40% of maximal voluntary contraction of the plantar flexors and knee extensors. Surface electromyography was recorded from the MG and VL and decomposed into the firing events of motor units (MUs). Statistical procedures were performed on the composite recruitment thresholds (RTs), ISIs and MUAPAMPS of recorded MUs collapsed across subjects and the y-intercepts and slopes calculated from each subject's ISI and MUAPAMP vs. RT relationships. Ultrasound was used to assess mCSA, echo intensity (mEI), and subcutaneous fat (sFAT) of the MG and VL. The OF had greater mCSAs, mEI and sFAT (P=0.004-0.024), but there were no differences in mCSA when accounting for mEI for the MG (P=0.506) and VL (P=0.326). The NW children had significantly greater composite MUAPAMPS for the VL and MG (P<0.001), but only significantly larger MUAPAMPS of the VL remained for the NW (P<0.001) when subjects were matched for sFAT. There were no differences between groups for the ISI or MUAPAMP vs. RT relationships (P>0.05). These findings suggest that the OF children did not undergo significant muscle or MU hypertrophy that would be routinely activated during activities of daily living.

Clinicopathological study of intestinal smooth muscles, interstitial cells of Cajal, and enteric neurons in neonatal jejuno-ileal atresia with special reference to muscle morphometry

To assess the thickness of the intestinal smooth muscle layer and analyze the distribution and density of interstitial cells of Cajal (ICC) and enteric neurons in the proximal and distal segments of neonatal jejuno-ileal atresia. This is an observational study done over a period of one year in which fifteen cases of jejuno-ileal atresia were included. All the cases underwent laparotomy and resection of the atretic segment with variable portions of the dilated proximal segment and distal segment. Histopathological analysis was done on the sections taken from proximal segments (at 3 cm, 5 cm & 8 cm) and the distal segment (at 2 cm) from the atretic portion. The mean thickness of the inner circular muscle layer (ICML) and outer longitudinal muscle layer (OLML) was assessed in the above segments using image morphometry. In addition, we also analyzed the distribution and density of the ICCs and enteric neurons in the different segments using immunohistochemistry for c-kit and S-100, respectively. Controls included normal jejuno-ileal segments resected from postmortem cases (n=7) and other nonrelated surgeries (n=3). The findings were then compared with each-other and with normal controls. Mean thickness of ICML and OLML of the proximal segments at 8 cm was significantly lower than at 3 cm and 5 cm of ileal and jejunal atresias (p≪ 0.5). The mean thickness of ICML and OLML of distal segments at 2 cm was similar to the controls in all the atretic cases (p≫ 0.5). The mean ICML thickness at proximal 8 cm segment was similar to the distal segment of both ileal & jejunal atresias (p= 0.06 & 0.37 respectively). The mean thickness of the OLML of the proximal 8 cm segments was significantly more than that at the distal segment (p=0.008) in ileal atresias but was similar in cases of jejunal atresias (p=0.07). Both the proximal and distal segments of ileal as well as jejunal atresias showed reduction in distribution and density of ICCs, as compared to normal controls. The density of ICCs in proximal segments at 3 cm and 5 cm was similar in both ileal (p=0.33) and jejunal segments (p=0.41) but was significantly lower than the proximal 8 cm segments (p≪0.05).The distribution of ICCs in the proximal segment at 8 cm was similar to the distal segments (p≪0.05). S-100 staining showed dense expression of neurons and glial cells with presence of submucosal giant ganglia within the proximal dilated segments as compared to the distal segments and the controls, which were more marked at 3 cm and 5 cm levels than at 8 cm level. Muscle morphometry using image analysis is a simple technique to assess the thickness of the intestinal smooth muscle layers. There is significant smooth muscle hypertrophy along with marked alteration in density and distribution of ICCs and ENS in the dilated proximal segments up to 5 cm, and relatively milder changes at 8 cm levels, as compared to the distal segments and the controls. Prognosis study. Level II.

Genes Whose Gain or Loss-Of-Function Increases Skeletal Muscle Mass in Mice: A Systematic Literature Review.

Skeletal muscle mass differs greatly in mice and humans and this is partially inherited. To identify muscle hypertrophy candidate genes we conducted a systematic review to identify genes whose experimental loss or gain-of-function results in significant skeletal muscle hypertrophy in mice. We found 47 genes that meet our search criteria and cause muscle hypertrophy after gene manipulation. They are from high to small effect size: Ski, Fst, Acvr2b, Akt1, Mstn, Klf10, Rheb, Igf1, Pappa, Ppard, Ikbkb, Fstl3, Atgr1a, Ucn3, Mcu, Junb, Ncor1, Gprasp1, Grb10, Mmp9, Dgkz, Ppargc1a (specifically the Ppargc1a4 isoform), Smad4, Ltbp4, Bmpr1a, Crtc2, Xiap, Dgat1, Thra, Adrb2, Asb15, Cast, Eif2b5, Bdkrb2, Tpt1, Nr3c1, Nr4a1, Gnas, Pld1, Crym, Camkk1, Yap1, Inhba, Tp53inp2, Inhbb, Nol3, Esr1. Knock out, knock down, overexpression or a higher activity of these genes causes overall muscle hypertrophy as measured by an increased muscle weight or cross sectional area. The mean effect sizes range from 5 to 345% depending on the manipulated gene as well as the muscle size variable and muscle investigated. Bioinformatical analyses reveal that Asb15, Klf10, Tpt1 are most highly expressed hypertrophy genes in human skeletal muscle when compared to other tissues. Many of the muscle hypertrophy-regulating genes are involved in transcription and ubiquitination. Especially genes belonging to three signaling pathways are able to induce hypertrophy: (a) Igf1-Akt-mTOR pathway, (b) myostatin-Smad signaling, and (c) the angiotensin-bradykinin signaling pathway. The expression of several muscle hypertrophy-inducing genes and the phosphorylation of their protein products changes after human resistance and high intensity exercise, in maximally stimulated mouse muscle or in overloaded mouse plantaris.

Physical activity and Mediterranean diet based on olive tree phenolic compounds from two different geographical areas have protective effects on early osteoarthritis, muscle atrophy and hepatic steatosis.

Osteoarthitis (OA) leads to progressive loss of articular cartilage, pain and joint disability. An acute injury constitutes an important risk factor for early OA, determining an inflammatory process responsible of cartilage degeneration and muscle atrophy, due to the joint pain and immobility. The study aims to assess the effects of conjugation of physical activity and diet enriched by olive tree compounds [extra virgin olive oil (EVOO) and olive leaf extract (OLE)], on the musculoskeletal system in OA rat model. OA was induced by anterior cruciate ligament transection and confirmed by Mankin and OARSI scores. Rats were subjected to physical activity on treadmill 5 days a week for 10min daily and fed with experimental diets (standard diet enriched with Sicilian EVOO, Tunisian EVOO and Tunisian EVOO-OLE) for 12 weeks. Immunohistochemistry was used to evaluate IL-6 and lubricin expression in cartilage tissue and ELISA was used to quantify these proteins in serum at different time points. Histology and histomorphometry analysis were done to valuate liver steatosis, muscle atrophy and cartilage pathological changes. Compared to the OA group, the experimental groups showed general increased lubricin and decreased IL-6 expression, significant muscle hypertrophy and no signs of liver steatosis, suggesting the beneficial effects of physical activity coupled with EVOO-enriched diets on rat articular cartilage. Interestingly, the best result was shown for Sicilian EVOO-enriched diet. In conclusion, the conjugation of physical activity and EVOO-enriched diet determines a significant articular cartilage recovery process in early OA.

P.476 - Muscle hyperthrophy with RYR1 mutation

We report 4 members of the same family with muscle hypertrophy and cramps. They all presented with hip dysplasia at birth and rapidly developed significant muscle hypertrophy in infancy with unusual strength. The older members later developed refractory cramps despite Dantrolene. Some presented spontaneous rhabdomyolysis and heat intolerance during summer. Non dystrophic myotonias genes were tested and came back negative They were all found with an autosomal dominant known RYR1 mutation (p.Arg4737Trp). Muscle biopsy demonstrated absence of cores and only mid hypertrophic fibres. To our knowledge only one family with muscle hypertrophy and RYR1 mutation has been reported. We are investigating to see if this new phenotype is really only due to RYR mutation or a second hit in the excitation coupling contraction system. Whole exome sequencing is still pending as well as functional analysis to see the real impact of this mutation on Ryanodine channel to explain the phenotype. These cases are interesting to show the major role of RYR1 on muscle size and power potentially opening new ways for treatment of congenital myopathies.

Extraocular Muscle Compartments in Superior Oblique Palsy.

PurposeTo investigate changes in volumes of extraocular muscle (EOM) compartments in unilateral superior oblique (SO) palsy using magnetic resonance imaging (MRI).MethodsHigh-resolution, surface-coil MRI was obtained in 19 patients with unilateral SO palsy and 19 age-matched orthotropic control subjects. Rectus EOMs and the SO were divided into two anatomic compartments for volume analysis in patients with unilateral SO palsy, allowing comparison of total compartmental volumes versus controls. Medial and lateral compartmental volumes of the SO muscle were compared in patients with isotropic (round shape) versus anisotropic (elongated shape) SO atrophy.ResultsThe medial and lateral compartments of the ipsilesional SO muscles were equally atrophic in isotropic SO palsy, whereas the lateral compartment was significantly smaller than the medial in anisotropic SO palsy (P = 0.01). In contrast to the SO, there were no differential compartmental volume changes in rectus EOMs; however, there was significant total muscle hypertrophy in the ipsilesional inferior rectus (IR) and lateral rectus (LR) muscles and contralesional superior rectus (SR) muscles. Medial rectus (MR) volume was normal both ipsi- and contralesionally.ConclusionsA subset of patients with SO palsy exhibit selective atrophy of the lateral, predominantly vertically acting SO compartment. Superior oblique atrophy is associated with whole-muscle volume changes in the ipsilesional IR, ipsilesional LR, and contralesional SR; however, SO muscle atrophy is not associated with compartmentally selective volume changes in the rectus EOMs. Selective compartmental SO pathology may provide an anatomic mechanism that explains some of the variability in clinical presentations of SO palsy.

Effect of Progressive Resistance Training on Measures of Skeletal Muscle Hypertrophy, Muscular Strength and Health-Related Quality of Life in Patients with Chronic Kidney Disease: A Systematic Review and Meta-Analysis

Skeletal muscle wasting resulting in reduced muscular strength and health-related quality of life (HR-QOL) is common in chronic kidney disease (CKD) and may be reversed with progressive resistance training (PRT). Therefore, we systematically assessed the effect of PRT on measures of skeletal muscle hypertrophy, muscular strength and HR-QOL in this cohort to inform clinical practice and guidelines. We performed a systematic review and meta-analysis. We included randomised controlled trials (RCTs) that investigated the independent effect of PRT (>6 weeks) on measures of skeletal muscle hypertrophy [muscle mass or cross-sectional area (CSA)], muscular strength and/or HR-QOL in adults with CKD. The standardised mean difference (SMD) from each study was pooled to produce an overall estimate of effect and associated 95% confidence interval (95% CI) between treatment and control groups on primary outcomes. Seven RCTs in 271 patients with Stage 3-5 CKD yielded seven studies on muscular strength (N = 249), six studies on total body muscle mass (N = 200) and six studies on HR-QOL (N = 223). PRT significantly improved standardised muscular strength [SMD 1.15 (95% CI 0.80-1.49)] and HR-QOL [SMD 0.83 (95% CI 0.51-1.16)], but not total body muscle mass [SMD 0.29 (95% CI -0.27 to 0.86)] in our primary analysis. However, secondary analysis of six studies showed that PRT induced significant muscle hypertrophy of the lower extremities (leg mass, or mid-thigh or quadriceps CSA) [SMD 0.43 (95% CI 0.11-0.76)], a pertinent analysis given that most studies implemented lower-body PRT only. Robust evidence from RCTs indicates that PRT can induce skeletal muscle hypertrophy and increase muscular strength and HR-QOL outcomes in men and women with CKD. Therefore, clinical practice guidelines should be updated to inform clinicians on the benefits of PRT in this cohort.

Viral expression of insulin-like growth factor I E-peptides increases skeletal muscle mass but at the expense of strength

Insulin-like growth factor I (IGF-I) is a protein that regulates and promotes growth in skeletal muscle. The IGF-I precursor polypeptide contains a COOH-terminal extension called the E-peptide. Alternative splicing in the rodent produces two isoforms, IA and IB, where the mature IGF-I in both isoforms is identical yet the E-peptides, EA and EB, share less than 50% homology. Recent in vitro studies show that the E-peptides can enhance IGF-I signaling, leading to increased myoblast cell proliferation and migration. To determine the significance of these actions in vivo and to evaluate if they are physiologically beneficial, EA and EB were expressed in murine skeletal muscle via viral vectors. The viral constructs ensured production of E-peptides without the influence of additional IGF-I through an inactivating mutation in mature IGF-I. E-peptide expression altered ERK1/2 and Akt phosphorylation and increased satellite cell proliferation. EB expression resulted in significant muscle hypertrophy that was IGF-I receptor dependent. However, the increased mass was associated with a loss of muscle strength. EA and EB have similar effects in skeletal muscle signaling and on satellite cells, but EB is more potent at increasing muscle mass. Although sustained EB expression may drive hypertrophy, there are significant physiological consequences for muscle.

Low-Load Bench Press Training to Fatigue Results in Muscle Hypertrophy Similar to High-Load Bench Press Training

The purpose of this study was to determine whether the training responses observed with low-load resistance exercise to volitional fatigue translates into significant muscle hypertrophy, and compare that response to high-load resistance training. Nine previously untrained men (aged 25 [SD 3] years at the beginning of the study, standing height 1.73 [SD 0.07] m, body mass 68.9 [SD 8.1] kg) completed 6-week of high load-resistance training (HL-RT) (75% of one repeti-tion maximal [1RM], 3-sets, 3x/wk) followed by 12 months of detraining. Following this, subjects completed 6 weeks of low load-resistance training (LL-RT) to volitional fatigue (30% 1 RM, 4 sets, 3x/wk). Increases (p 0.05) in magnetic resonance imaging-measured triceps brachii and pectorals major muscle cross-sectional areas were similar for both HL-RT (11.9% and 17.6%, respectively) and LL-RT (9.8% and 21.1%, respectively). In addition, both groups increased (p 0.05) 1RM and maximal elbow extension strength following training; however, the percent increases in 1RM (8.6% vs. 21.0%) and elbow extension strength (6.5% vs. 13.9%) were significantly (p 0.05) lower with LL-RT. Both protocols elicited similar increases in muscle cross-sectional area, however differences were observed in strength. An explanation of the smaller relative increases in strength may be due to the fact that detraining after HL-RT did not cause strength values to return to baseline levels thereby producing smaller changes in strength. In addition, the results may also suggest that the consistent practice of lifting a heavy load is necessary to maximize gains in muscular strength of the trained movement. These results demonstrate that significant muscle hypertrophy can occur without high-load resistance training and suggests that the focus on percentage of external load as the important deciding factor on muscle hypertrophy is too simplistic and inappropriate.

Time course for arm and chest muscle thickness changes following bench press training

The purpose of this study was to investigate the time course of hypertrophic adaptations in both the upper arm and trunk muscles following high-intensity bench press training. Seven previously untrained young men (aged 25 ± 3 years) performed free-weight bench press training 3 days (Monday, Wednesday and Friday) per week for 24 weeks. Training intensity and volume were set at 75% of one repetition maximum (1-RM) and 30 repetitions (3 sets of 10 repetitions, with 2-3 min of rest between sets), respectively. Muscle thickness (MTH) was measured using B-mode ultrasound at three sites: the biceps and triceps brachii and the pectoralis major. Measurements were taken a week prior to the start of training, before the training session on every Monday and 3 days after the final training session. Pairwise comparisons from baseline revealed that pectoralis major MTH significantly increased after week-1 (p = 0.002), triceps MTH increased after week-5 (p = 0.001) and 1-RM strength increased after week-3 (p = 0.001) while no changes were observed in the biceps MTH from baseline. Significant muscle hypertrophy was observed earlier in the chest compared to that of the triceps. Our results indicate that the time course of the muscle hypertrophic response differs between the upper arm and chest.

Adeno-Associated Viral (AAV)-Mediated Follistatin (FS) Gene Transfer Toxicology Studies in Preparation for Phase I Clinical Trial (SC02.004)

Objective: Establish safety of rAAV.CMV.FS gene transfer by intramuscular (i.m.) injection for improving quadriceps strength in preparation for phase I clinical trial. Background FS is a potent myostatin inhibitor that increases muscle size and strength in mice and non-human primates when secreted by muscle following delivery by AAV. Safety concerns have included impeded release of pituitary-gonadal axis hormones and general organ toxicity. In this study we used a non-tissue binding FS isoform (FS344) to address these safety concerns in mice at viral doses 10-fold greater than those planned for clinical use. Design/Methods: Mice were randomized to three experimental arms with bilateral i.m. injections to quadriceps muscle of rAAV1.CMV.FS344 equal to highest clinical dose (2.0e12 vg/kg) or 10-fold higher (2.0e13 vg/kg). Animals were followed to sacrifice time points at 6-,12-,24-, and 36-weeks (5 animals/sex/cohort/timepoint) post-injection (p.i.). Outcomes included: bodyweight, hematology, chemistry panels, pituitary-gonadal hormones; immune studies, and histopathology of 24 organs from each animal. Results: No treatment-related adverse clinical or toxicology signs were observed and viral DNA in non-injected tissues dissipated by 24 weeks. Within 6 weeks, high dose animals showed scattered focal infiltrates of inflammatory cells corresponding to T-cell immunity to AAV1 identified by IFN-γ ELISpot, but no other pathology was observed. Wet weights of quadriceps increased by 3.5-fold at 36 weeks p.i. in high dose animals. Muscle fiber hypertrophy was observed at 6 weeks and fiber diameter increased by 50% compared to controls by 36 weeks. Hypertrophic-multinucleated fibers were observed at 12 weeks p.i. with increased density of PAX7 positive nuclei. Conclusions: This study shows rAAV1.CMV.FS344 is safe and well tolerated at the proposed clinical doses and causes satellite cell proliferation and significant muscle hypertrophy by fusion with differentiated satellite cells. Early transient inflammation in muscle is related to immune response to AAV1. These results support this approach for clinical trial use. Supported by: Grants from The Myositis Association and Parent Project Muscular Dystrophy, Inc; and support from the Foundation at Nationwide Children9s Hospital. Disclosure: Dr. Kota has nothing to disclose. Dr. Shilling has nothing to disclose. Dr. Montgomery has nothing to disclose. Dr. Lewis has nothing to disclose. Dr. Bevan has nothing to disclose. Dr. Shontz has nothing to disclose. Dr. Kaminoh has nothing to disclose. Dr. Rosales has nothing to disclose. Dr. Viollet has nothing to disclose. Dr. Flanigan has received personal compensaiton for activities with AVI Therapeutics, Prosensa Therapeutics, and PTC, Inc. Dr. Flanigan has received research support from PTC Therapeutics. Dr. Clark has nothing to disclose. Dr. Kaspar has nothing to disclose. Dr. Sahenk has nothing to disclose. Dr. Mendell has received research support from AVI BioPharmaceuticals Inc.

Effects of Resistance Training on Adiposity and Metabolism after Spinal Cord Injury

This pilot work was conducted to evaluate the effects of neuromuscular electrical stimulation resistance training (RT) of the paralyzed knee extensor muscle groups on skeletal muscle and intramuscular fat (IMF) cross-sectional areas, trunk visceral adipose tissue (VAT), carbohydrate, and lipid profiles in men with spinal cord injury. Nine individuals with motor complete spinal cord injury were randomly assigned to an RT + diet group (n = 5) or a diet group (n = 4). The RT + diet underwent 12 wk of progressive RT, twice weekly, to the knee extensor muscle groups using neuromuscular electrical stimulation and ankle weights. Weekly feedback was provided to both groups to maintain a standard diet. Magnetic resonance imaging and a whole-body dual-energy x-ray absorptiometric images were obtained before and 1 wk after interventions. Participants underwent a metabolic study after a 12-h overnight fast to measure fasting and postchallenge plasma glucose, insulin, and lipid profiles. Skeletal muscle hypertrophy was detected in the whole thigh, knee extensors, and flexors in the RT + diet group compared with the diet group. VAT cross-sectional area, VAT/subcutaneous adipose tissue ratio at L5-S3, and percent IMF decreased significantly in the RT + diet group. Plasma insulin area under the curve decreased in the RT + diet group but not in the diet group. Fasting triglycerides and cholesterol/HDL decreased in the RT + diet group. Twice-weekly evoked RT to the paralyzed lower extremities resulted in significant skeletal muscle hypertrophy that was associated with reduction in VAT, VAT/subcutaneous adipose tissue ratio, and percent IMF. Significant improvements in insulin profile and lipid metabolism were noted in the RT + diet when compared with diet alone.

Effects of Two Different Half-Squat Training Programs on Fatigue During Repeated Cycling Sprints in Soccer Players

This study compared the effects of two different half-squat training programs on the repeated-sprint ability of soccer players during the preseason. Twenty male professional soccer players were divided into 2 groups: One group (S-group) performed 4 sets of 5 repetitions with 90% of their 1-repetition maximum (1RM), and the other group (H-group) performed 4 sets of 12 repetitions with 70% of 1RM, 3 times per week for 6 weeks, in addition to their common preseason training program. Repeated-sprint ability was assessed before and after training by 10 × 6-second cycle ergometer sprints separated by 24 seconds of passive recovery. Maximal half-squat strength increased significantly in both groups (p < 0.01), but this increase was significantly greater in the S-group compared with the H-group (17.3 ± 1.9 vs. 11.0 ± 1.9%, p < 0.05). Lean leg volume (LLV) increased only in the H-group. Total work over the 10 sprints improved in both groups after training, but this increase was significantly greater in the second half (8.9 ± 2.6%) compared with the first half of the sprint test (3.2 ± 1.7%) only in the S-group. Mean power output (MPO) expressed per liter of LLV was better maintained during the last 6 sprints posttraining only in the S-group, whereas there was no change in MPO per LLV in the H-group over the 10 sprints. These results suggest that resistance training with high loads is superior to a moderate-load program, because it increases strength without a change in muscle mass and also results in a greater improvement in repeated sprint ability. Therefore, resistance training with high loads may be preferable when the aim is to improve maximal strength and fatigue during sprinting in professional soccer players.

An examination of the time course of training-induced skeletal muscle hypertrophy

Skeletal muscle hypertrophy is typically considered to be a slow process. However, this is partly because the time course for hypertrophy has not been thoroughly examined. The purpose of this study was to use weekly testing to determine a precise time course of skeletal muscle hypertrophy during a resistance training program. Twenty-five healthy, sedentary men performed 8weeks of high-intensity resistance training. Whole muscle cross-sectional area (CSA) of the dominant thigh was assessed using a peripheral quantitative computed tomography scanner during each week of training (W1-W8). Isometric maximum voluntary contractions (MVC) were also measured each week. After only two training sessions (W1), the mean thigh muscle CSA increased by 5.0cm(2) (3.46%; p<0.05) from the pre-testing (P1) and continued to increase with each testing session. It is possible that muscular edema may have influenced the early CSA results. To adjust for this possibility, with edema assumedly at its highest at W1, the next significant increase from W1 was at W3. W4 was the first significant increase of MVC over P1. Therefore, significant skeletal muscle hypertrophy likely occurred around weeks 3-4. Overall, from the pre-testing to W8, there was an increase of 13.9cm(2) (9.60%). These findings suggested that training-induced skeletal muscle hypertrophy may occur early in a training program.