It is unknown if adult human skeletal muscle has an epigenetic memory of earlier encounters with growth. We report, for the first time in humans, genome-wide DNA methylation (850,000 CpGs) and gene expression analysis after muscle hypertrophy (loading), return of muscle mass to baseline (unloading), followed by later hypertrophy (reloading). We discovered increased frequency of hypomethylation across the genome after reloading (18,816 CpGs) versus earlier loading (9,153 CpG sites). We also identified AXIN1, GRIK2, CAMK4, TRAF1 as hypomethylated genes with enhanced expression after loading that maintained their hypomethylated status even during unloading where muscle mass returned to control levels, indicating a memory of these genes methylation signatures following earlier hypertrophy. Further, UBR5, RPL35a, HEG1, PLA2G16, SETD3 displayed hypomethylation and enhanced gene expression following loading, and demonstrated the largest increases in hypomethylation, gene expression and muscle mass after later reloading, indicating an epigenetic memory in these genes. Finally, genes; GRIK2, TRAF1, BICC1, STAG1 were epigenetically sensitive to acute exercise demonstrating hypomethylation after a single bout of resistance exercise that was maintained 22 weeks later with the largest increase in gene expression and muscle mass after reloading. Overall, we identify an important epigenetic role for a number of largely unstudied genes in muscle hypertrophy/memory.

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To better understand the effects of pubertal maturation on the contractile properties of skeletal muscle in vivo, the present study investigated whether there are any differences in the specific tension of the quadriceps muscle in 20 adults and 20 prepubertal children of both sexes. Specific tension was calculated as the ratio between the quadriceps tendon force and the sum of the physiological cross‐sectional area (PCSA) multiplied by the cosine of the angle of pennation of each head within the quadriceps muscle. The maximal quadriceps tendon force was calculated from the knee extension maximal voluntary contraction (MVC) by accounting for EMG‐based estimates of antagonist co‐activation, incomplete quadriceps activation using the interpolation twitch technique and magnetic resonance imaging (MRI)‐based measurements of the patellar tendon moment arm. The PCSA was calculated as the muscle volume, measured from MRI scans, divided by optimal fascicle length, measured from ultrasound images during MVC at the estimated angle of peak quadriceps muscle force. It was found that the quadriceps tendon force and PCSA of men (11.4 kN, 214 cm2) were significantly greater than those of the women (8.7 kN, 152 cm2; P < 0.01). Both adult groups had greater values than the children (P < 0.01) but there were no differences between boys (5.2 kN, 99 cm2) and girls (6.1 kN, 102 cm2). Agonist activation was greater in men and women than in girls (P < 0.05), and antagonist activation was greater in men than in boys (P < 0.05). Moment arm length was greater in men than in boys or girls and greater in women than in boys (P < 0.05). The angle of pennation did not differ between the groups in any of the quadriceps heads. The specific tension was similar (P > 0.05) between groups: men, 55 ± 11 N cm−2; women, 57.3 ± 13 N cm−2; boys, 54 ± 14 N cm−2; and girls, 59.8 ± 15 N cm−2. These findings indicate that the increased muscle strength with maturation is not due to an increase in the specific tension of muscle; instead, it can be attributed to increases in muscle size, moment arm length and voluntary activation level.

DNA methylation is an important epigenetic modification that can regulate gene expression following environmental encounters without changes to the genetic code. Using Infinium MethylationEPIC BeadChip Arrays (850,000 CpG sites) we analysed for the first time, DNA isolated from untrained human skeletal muscle biopsies (vastus lateralis) at baseline (rest) and immediately following an acute (single) bout of resistance exercise. In the same participants, we also analysed the methylome following a period of muscle growth (hypertrophy) evoked via chronic (repeated bouts-3 sessions/wk) resistance exercise (RE) (training) over 7-weeks, followed by complete exercise cessation for 7-weeks returning muscle back to baseline levels (detraining), and finally followed by a subsequent 7-week period of RE-induced hypertrophy (retraining). These valuable methylome data sets described in the present manuscript and deposited in an open-access repository can now be shared and re-used to enable the identification of epigenetically regulated genes/networks that are modified after acute anabolic stimuli and hypertrophy, and further investigate the phenomenon of epigenetic memory in skeletal muscle.

Muscle performance is closely related to the architecture and dimensions of the muscle-tendon unit and the effect of maturation on these architectural characteristics in humans is currently unknown. This study determined whether there are differences in musculo-tendinous architecture between adults and children of both sexes. Fascicle length and pennation angle were measured from ultrasound images at three sites along the length of the vastus intermedius, vastus lateralis, vastis medialis and rectus femoris muscles. Muscle volume and muscle-tendon length were measured from magnetic resonance images. Muscle physiological cross-sectional area (PCSA) was calculated as the ratio of muscle volume to optimum fascicle length. Fascicle length was greater in the adult groups than in children (P < 0.05) but pennation angle did not differ between groups (P > 0.05). The ratios between fascicle and muscle length and between fascicle and tendon length were not different (P > 0.05) between adults and children for any quadriceps muscle. Quadriceps volume and PCSA of each muscle were greater in adults than children (P < 0.01) but the relative proportion of each head to the total quadriceps volume was similar in all groups. However, the difference in PCSA between adults and children (men 104% greater than boys, women 57% greater than girls) was greater (P < 0.05) than the difference in fascicle length (men 37% greater than boys, women 10% greater than girls). It is concluded that the fascicle, muscle and tendon lengthen proportionally during maturation, thus the muscle-tendon stiffness and excursion range are likely to be similar in children and adults but the relatively greater increase in PCSA than fascicle length indicates that adult muscles are better designed for force production than children's muscles.

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The present study investigated whether differences between adults and children in mechanical power during single-joint knee extension tasks and the complex multijoint task of jumping could be explained by differences in the quadriceps femoris muscle volume. Peak power was calculated during squat jumps, from the integral of the vertical force measured by a force plate, and during concentric knee extensions at 30, 90, 120, 180 and 240 deg·s −1 , and muscle volume was measured from magnetic resonance images for 10 men, 10 women, 10 prepubertal boys and 10 prepubertal girls. Peak power during jumping and isokinetic knee extension was significantly higher in men than in women, and in both adult groups compared with children (P < 0.01), although there were no differences between boys and girls. When power was normalized to muscle volume, the intergroup differences ceased to exist for both tasks. Peak power correlated significantly with quadriceps volume (P < 0.01), with r 2 values of 0.8, 0.86, 0.81, 0.78 and 0.81 from isokinetic knee extension at angular velocities of 30, 90, 120, 180 and 240 deg·s −1 , respectively, and with an r 2 value of 0.9 from squat jumps. These results indicate that the quadriceps femoris muscle volume accounts largely for the increase in power that occurs with maturation in the two genders not only in kinematically constrained knee extensions but also in multijoint tasks. Future studies should examine the role of other factors relating to the generation and transmission of contractile power, such as muscle architecture, tendon stiffness and external mechanical leverage.

Despite marked improvements in disease control (most patients achieving or approaching remission), the relative loss of MM and increased adiposity in RA patients compared with matched HCs was similar to that observed pre-T2T. Additionally, performance of objective function tests was unchanged from that reported by our group for pre-T2T RA patients. Thus T2T, even in responsive RA patients, did not attenuate rheumatoid cachexia or improve objectively assessed function.