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Tanimoto, M, Sanada, K, Yamamoto, K, Kawano, H, Gando, Y, Tabata, I, Ishii, N, and Miyachi, M. Effects of whole-body low-intensity resistance training with slow movement and tonic force generation on muscular size and strength in young men. J Strength Cond Res 22(6)1926-1938, 2008-Our previous study showed that relatively low-intensity (~50% one-repetition maximum [1RM]) resistance training (knee extension) with slow movement and tonic force generation (LST) caused as significant an increase in muscular size and strength as high-intensity (~80% 1RM) resistance training with normal speed (HN). However, that study examined only local effects of one type of exercise (knee extension) on knee extensor muscles. The present study was performed to examine whether a whole-body LST resistance training regimen is as effective on muscular hypertrophy and strength gain as HN resistance training. Thirty-six healthy young men without experience of regular resistance training were assigned into three groups (each n = 12) and performed whole-body resistance training regimens comprising five types of exercise (vertical squat, chest press, latissimus dorsi pull-down, abdominal bend, and back extensionthree sets each) with LST (~55-60% 1RM, 3 seconds for eccentric and concentric actions, and no relaxing phase); HN (~80-90% 1RM, 1 second for concentric and eccentric actions, 1 second for relaxing); and a sedentary control group (CON). The mean repetition maximum was eight-repetition maximum in LST and HN. The training session was performed twice a week for 13 weeks. The LST training caused significant (p < 0.05) increases in whole-body muscle thickness (6.8 ± 3.4% in a sum of six sites) and 1RM strength (33.0 ± 8.8% in a sum of five exercises) comparable with those induced by HN training (9.1 ± 4.2%, 41.2 ± 7.6% in each measurement item). There were no such changes in the CON group. The results suggest that a whole-body LST resistance training regimen is as effective for muscular hypertrophy and strength gain as HN resistance training.

Skeletal muscle formation occurs through fusion of myoblasts to form multinucleated myofibers. From a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) loss-of-function screen for genes required for myoblast fusion and myogenesis, we discovered an 84–amino acid muscle-specific peptide that we call Myomixer. Myomixer expression coincides with myoblast differentiation and is essential for fusion and skeletal muscle formation during embryogenesis. Myomixer localizes to the plasma membrane, where it promotes myoblast fusion and associates with Myomaker, a fusogenic membrane protein. Myomixer together with Myomaker can also induce fibroblast-fibroblast fusion and fibroblast-myoblast fusion. We conclude that the Myomixer-Myomaker pair controls the critical step in myofiber formation during muscle development.

Wilborn, CD, Taylor, LW, Greenwood, M, Kreider, RB, and Willoughby, DS. Effects of different intensities of resistance exercise on regulators of myogenesis. J Strength Cond Res 23(8)2179-2187, 2009-A single bout of high-intensity resistance exercise is capable of activating the expression of various genes in skeletal muscle involved in hypertrophy such as myosin heavy chain (MHC) isoforms, myogenic regulatory factors (MRFs), and growth factors. However, the specific role exercise intensity plays on the expression of these genes is not well defined. The purpose of this study was to investigate the effects of exercise intensity on MHC (type I, IIA, IIX), MRF (Myo-D, myogenin, MRF-4, myf5), and growth factor (insulin-like growth factor [IGF]-1, IGF-1 receptor [IGF-R1], mechano-growth factor [MGF]) mRNA expression. Thirteen male participants (21.5 ± 2.9 years, 86.1 ± 19.5 kg, 69.7 ± 2.7 in.) completed bouts of resistance exercise involving 4 sets of 18-20 repetitions with 60-65% 1 repetition maximum (1RM) and 4 sets of 8-10 repetitions with 80-85% 1RM. Vastus lateralis biopsies were obtained immediately before exercise, and at 30 minutes, 2 hours, and 6 hours after each bout. The levels of mRNA expression were determined using real-time polymerase chain reaction. Data were analyzed using 2 × 4 multivariate analysis of variance (p ≤ 0.05). For both intensities, MHC type IIX, IGF-1, IGF-R1, MGF, Myo-D, myogenin, MRF-4, and myf5 mRNA were all significantly increased in response to resistance exercise by 2 hours after exercise, whereas myostatin and the cyclin-dependent kinase inhibitor p27 were decreased at 2 hours after exercise (p < 0.05). Resistance exercise between 60-85% 1RM upregulates the mRNA expression of MHC and factors involved in myogenic activation of satellite cells while concomitantly decreasing expression of myogenic inhibitors.

Vitamin D is well known for its regulatory role in calcium and phosphate homeostasis, but its role in muscle mass and strength during growth remains inconclusive. We explored the association of serum 25-hydroxyvitamin D (25(OH)D) with muscle development in girls from 11 to 18-years old. Whole body lean tissue mass (LMWB), appendicular lean mass (aLM), muscle cross-sectional area at the lower leg (mCSA), maximal voluntary contraction of elbow flexors (MVC elbow) and knee extensors (MVC knee) were assessed in 217 girls aged 10-13 years (at baseline), 215 in 2-year and 226 in 7.5-year follow-up. Serum concentration of 25(OH)D and intact parathyroid hormone (PTH) were analyzed retrospectively and girls were categorized according to their 25(OH)D levels (consistently insufficient 25(OH)D GLL <50 nmol/l and consistently sufficient GHH >50 nmol/l from baseline to 7-year follow-up). We found that 25(OH)D level declined until menarche (p<0.05) while LMWB, aLM, mCSA, MVC elbow and MVC knee continued to increase (p<0.001 for all) post menarche. At pre-menarche, the GLL (n = 34) had higher LMWB and aLM than the GHH (n = 21, p<0.05), while post-menarche the GHH (n = 15) had a greater catch-up gain in LMWB (p = 0.004), aLM (p = 0.001) and mCSA (p = 0.027) compared to the GLL (n = 65) over the first 2-year period. At the age of 18, no differences in muscle mass/strength between the low (n = 151) and high (n = 77) levels of 25(OH)D groups were found. This finding was independent of vitamin D receptor genotype and other confounders. In conclusion, our results showed that levels of 25(OH)D have no significant negative influence on the development of muscle mass and strength during pubertal growth both with longitudinal and cross-sectional comparison. On the contrary, our results suggest that the temporary negative association between 25(OH)D and muscle mass arises as a consequence of fast growth prior to menarche, and this negative association is diminished through catch-up growth after menarche.

Extensive analyses of mice carrying null mutations in paired box 7 (Pax7) have confirmed the progressive loss of the satellite cell lineage in skeletal muscle, resulting in severe muscle atrophy and death. A recent study using floxed alleles and tamoxifen-induced inactivation concluded that after 3 wk of age, Pax7 was entirely dispensable for satellite cell function. Here, we demonstrate that Pax7 is an absolute requirement for satellite cell function in adult skeletal muscle. Following Pax7 deletion, satellite cells and myoblasts exhibit cell-cycle arrest and dysregulation of myogenic regulatory factors. Maintenance of Pax7 deletion through continuous tamoxifen administration prevented regrowth of Pax7-expressing satellite cells and a profound muscle regeneration deficit that resembles the phenotype of skeletal muscle following genetically engineered ablation of satellite cells. Therefore, we conclude that Pax7 is essential for regulating the expansion and differentiation of satellite cells during both neonatal and adult myogenesis.

Schoenfeld, BJ. The mechanisms of muscle hypertrophy and their application to resistance training. J Strength Cond Res 24(10)2857-2875, 2010-The quest to increase lean body mass is widely pursued by those who lift weights. Research is lacking, however, as to the best approach for maximizing exercise-induced muscle growth. Bodybuilders generally train with moderate loads and fairly short rest intervals that induce high amounts of metabolic stress. Powerlifters, on the other hand, routinely train with high-intensity loads and lengthy rest periods between sets. Although both groups are known to display impressive muscularity, it is not clear which method is superior for hypertrophic gains. It has been shown that many factors mediate the hypertrophic process and that mechanical tension, muscle damage, and metabolic stress all can play a role in exercise-induced muscle growth. Therefore, the purpose of this paper is twofold(a) to extensively review the literature as to the mechanisms of muscle hypertrophy and their application to exercise training and (b) to draw conclusions from the research as to the optimal protocol for maximizing muscle growth.

An algorithm uncovers transcriptome dynamics during differentiation by ordering RNA-Seq data from single cells. Defining the transcriptional dynamics of a temporal process such as cell differentiation is challenging owing to the high variability in gene expression between individual cells. Time-series gene expression analyses of bulk cells have difficulty distinguishing early and late phases of a transcriptional cascade or identifying rare subpopulations of cells, and single-cell proteomic methods rely on a priori knowledge of key distinguishing markers 1 . Here we describe Monocle, an unsupervised algorithm that increases the temporal resolution of transcriptome dynamics using single-cell RNA-Seq data collected at multiple time points. Applied to the differentiation of primary human myoblasts, Monocle revealed switch-like changes in expression of key regulatory factors, sequential waves of gene regulation, and expression of regulators that were not known to act in differentiation. We validated some of these predicted regulators in a loss-of function screen. Monocle can in principle be used to recover single-cell gene expression kinetics from a wide array of cellular processes, including differentiation, proliferation and oncogenic transformation.

Tissue-engineered skeletal muscle can serve as a physiological model of natural muscle and a potential therapeutic vehicle for rapid repair of severe muscle loss and injury. Here, we describe a platform for engineering and testing highly functional biomimetic muscle tissues with a resident satellite cell niche and capacity for robust myogenesis and self-regeneration in vitro. Using a mouse dorsal window implantation model and transduction with fluorescent intracellular calcium indicator, GCaMP3, we nondestructively monitored, in real time, vascular integration and the functional state of engineered muscle in vivo. During a 2-wk period, implanted engineered muscle exhibited a steady ingrowth of blood-perfused microvasculature along with an increase in amplitude of calcium transients and force of contraction. We also demonstrated superior structural organization, vascularization, and contractile function of fully differentiated vs. undifferentiated engineered muscle implants. The described in vitro and in vivo models of biomimetic engineered muscle represent enabling technology for novel studies of skeletal muscle function and regeneration.

Following skeletal muscle damage, a population of resident fibro/adipogenic progenitors (FAP) initiates proliferation, resulting in the generation of ectopic white fat but not myofibres. FAPs enhance the differentiation of the myogenic progenitors involved in muscle regeneration. Efficient tissue regeneration is dependent on the coordinated responses of multiple cell types. Here, we describe a new subpopulation of fibro/adipogenic progenitors (FAPs) resident in muscle tissue but arising from a distinct developmental lineage. Transplantation of purified FAPs results in the generation of ectopic white fat when delivered subcutaneously or intramuscularly in a model of fatty infiltration, but not in healthy muscle, suggesting that the environment controls their engraftment. These cells are quiescent in intact muscle but proliferate efficiently in response to damage. FAPs do not generate myofibres, but enhance the rate of differentiation of primary myogenic progenitors in co-cultivation experiments. In summary, FAPs expand upon damage to provide a transient source of pro-differentiation signals for proliferating myogenic progenitors.

Resident tissue stem cells called satellite cells repair muscle after injury. However, how satellite cells operate inside living tissue is unclear. Gurevich et al. exploited the optical clarity of zebrafish larvae and used a series of genetic approaches to study muscle injury. After injury, satellite cells divide asymmetrically to generate a progenitor pool for muscle replacement and at the same time “self-renew” the satellite stem cell. This results in regeneration that is highly clonal in nature, validating many decades of in vitro analyses examining the regenerative capacity of skeletal muscle. Science , this issue p. 136 The visualization of myogenic repair in zebrafish muscle reveals a dynamic regeneration process in living animals. Skeletal muscle is an example of a tissue that deploys a self-renewing stem cell, the satellite cell, to effect regeneration. Recent in vitro studies have highlighted a role for asymmetric divisions in renewing rare “immortal” stem cells and generating a clonal population of differentiation-competent myoblasts. However, this model currently lacks in vivo validation. We define a zebrafish muscle stem cell population analogous to the mammalian satellite cell and image the entire process of muscle regeneration from injury to fiber replacement in vivo. This analysis reveals complex interactions between satellite cells and both injured and uninjured fibers and provides in vivo evidence for the asymmetric division of satellite cells driving both self-renewal and regeneration via a clonally restricted progenitor pool.