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Insulin-like growth factor-I (IGF-I) and its splice variants Insulin-like growth factor-I isoform Ea (IGF-IEa) and mechano growth factor (MGF) may play an important role in muscular adaptations to resistance training (RT) that may be modulated by ageing. It has been suggested that IGF-I induces cellular responses via AKT8 virus oncogene cellular homolog (Akt) and Extracellular signal-regulated kinase (Erk) signalling pathways. Therefore, resistance exercise-induced changes in skeletal muscle IGF-IEa and MGF messenger ribonucleic acid (mRNA), and MGF, Erk1/2, Akt and p70S6K protein expression were investigated before and after 21 weeks of RT in younger (YM, 20-34 yrs., n = 7) and older men (OM, 51-71 yrs., n = 10). Experimental resistance exercises (RE) of 5 × 10 repetition maximum leg presses were performed pre- and post-RT. Muscle biopsies were obtained before and 48 h after REs, to study the late response to muscle loading. The muscle proteins or mRNAs of interest were not systematically influenced by the REs or RT, except for MGF mRNA expression which was increased (p < .01) following RE before RT in OM. No differences were observed between YM and OM in any variables. This study demonstrated that basal levels or RE-induced responses in skeletal muscle MGF, Erk1/2, Akt and p70S6K protein levels or IGF-IEa and MGF mRNA expression did not differ between YM and OM, nor change systematically due to RT. Thus, ageing appears not to effect expression of the present signalling molecules involved in skeletal muscle hypertrophy.

MiRNAs are fine-tuning modifiers of skeletal muscle regulation, but knowledge of their hormonal control is lacking. We used a co-twin case-control study design, that is, monozygotic postmenopausal twin pairs discordant for estrogen-based hormone replacement therapy (HRT) to explore estrogen-dependent skeletal muscle regulation via miRNAs. MiRNA profiles were determined from vastus lateralis muscle of nine healthy 54-62-years-old monozygotic female twin pairs discordant for HRT (median 7 years). MCF-7 cells, human myoblast cultures and mouse muscle experiments were used to confirm estrogen's causal role on the expression of specific miRNAs, their target mRNAs and proteins and finally the activation of related signaling pathway. Of the 230 miRNAs expressed at detectable levels in muscle samples, qPCR confirmed significantly lower miR-182, miR-223 and miR-142-3p expressions in HRT using than in their nonusing co-twins. Insulin/IGF-1 signaling emerged one common pathway targeted by these miRNAs. IGF-1R and FOXO3A mRNA and protein were more abundantly expressed in muscle samples of HRT users than nonusers. In vitro assays confirmed effective targeting of miR-182 and miR-223 on IGF-1R and FOXO3A mRNA as well as a dose-dependent miR-182 and miR-223 down-regulations concomitantly with up-regulation of FOXO3A and IGF-1R expression. Novel finding is the postmenopausal HRT-reduced miRs-182, miR-223 and miR-142-3p expression in female skeletal muscle. The observed miRNA-mediated enhancement of the target genes' IGF-1R and FOXO3A expression as well as the activation of insulin/IGF-1 pathway signaling via phosphorylation of AKT and mTOR is an important mechanism for positive estrogen impact on skeletal muscle of postmenopausal women., (© 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

A thorough understanding of the role of estrogens on aging-related muscle weakness is lacking. To clarify the molecular mechanisms underlying the effects of hormone replacement therapy (HRT) on skeletal muscle, we analyzed systemic protein and local mRNA levels of factors related to interleukin 6 (IL-6) and insulin-like growth factor 1 (IGF-1) pathways in 30- to 35-year-old (n = 14) women (without hormonal contraceptives) and in 54- to 62-year-old monozygotic female twin pairs discordant for HRT (n = 11 pairs, mean duration of HRT 7.3 ± 3.7 years). Biopsies were taken from vastus lateralis muscle and from abdominal adipose tissue. We found, first, that the systemic levels of IL-6 receptors sIL-6R and sgp130 are sensitive to both age and HRT concomitant with the changes in body composition. The serum levels of sgp130 and sIL-6R were 16% and 52% (p ≤ 0.001 for both variables) higher in postmenopausal women than in premenopausal women, and 10% and 9% lower (p = 0.033 and p < 0.001, respectively) in the HRT using than in their non using co-twins. After adjustment for body fat amount, the differences were no more significant. Second, the transcript analyses emphasize the impact of adipose tissue on systemic levels of IL-6, sgp130 and sIL6R, both at pre- and postmenopausal age. In muscle, the most notable changes were 28% lower gene expression of IGF-1 splice variant Ea (IGF-1Ea) and 40% lower expression of splice variant Ec (IGF-1Ec) in the postmenopausal non-users than in premenopausal women (p = 0.016 and 0.019, respectively), and 28% higher expression of IGF1-receptor in HRT users than in non-users (p = 0.060). The results tend to demonstrate that HRT has positive anti-catabolic effect on aging skeletal muscle.

Aging is associated with gradual decline of skeletal muscle strength and mass often leading to diminished muscle quality. This phenomenon is known as sarcopenia and affects about 30% of the over 60-year-old population. Androgens act as anabolic agents regulating muscle mass and improving muscle performance. The role of female sex steroids as well as the ability of skeletal muscle tissue to locally produce sex steroids has been less extensively studied. We show that despite the extensive systemic deficit of sex steroid hormones in postmenopausal compared to premenopausal women, the hormone content of skeletal muscle does not follow the same trend. In contrast to the systemic levels, muscle tissue of post- and premenopausal women had similar concentrations of dehydroepiandrosterone and androstenedione, while the concentrations of estradiol and testosterone were significantly higher in muscle of the postmenopausal women. The presence of steroidogenetic enzymes in muscle tissue indicates that the elevated postmenopausal steroid levels in skeletal muscle are because of local steroidogenesis. The circulating sex steroids were associated with better muscle quality while the muscle concentrations reflected the amount of infiltrated fat within muscle tissue. We conclude that systemically delivered and peripherally produced sex steroids have distinct roles in the regulation of neuromuscular characteristics during aging., (© 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.)

Effects of heavy resistance exercise on serum testosterone and skeletal muscle androgen receptor (AR) concentrations were examined before and after a 21-week resistance training period. Seven healthy untrained young adult men (YT) and ten controls (YC) as well as ten older men (OT) and eight controls (OC) volunteered as subjects. Heavy resistance exercise bouts (5 × 10 RM leg presses) were performed before and after the training period. Muscle biopsies were obtained before and 1h and 48 h after the resistance exercise bouts from m.vastus lateralis (VL) to determine cross-sectional area of muscle fibers (fCSA) and AR mRNA expression and protein concentrations. No changes were observed in YC and OC while resistance training led to significant increases in maximal strength of leg extensors (1 RM), fCSA and lean body mass in YT and OT. Acute increases occurred in serum testosterone concentrations due to resistance exercises but basal testosterone remained unaltered. Mean AR mRNA expression and protein concentration remained unchanged after heavy resistance exercise bouts compared to pre-values. The individual pre- to post-training changes in resting (pre-exercise) AR protein concentration correlated with the changes in fCSA and lean body mass in the combined group of YT and OT. Similarly, it correlated with the changes in 1 RM in YT. Although mean AR expression did not changed due to the resistance exercise training, the present findings suggest that the individual changes of AR protein concentration in skeletal muscle following resistance training may have an impact on training-induced muscular adaptations in both younger and older men., (Copyright © 2010 Elsevier Inc. All rights reserved.)

High physical activity/aerobic fitness predicts low morbidity and mortality. Our aim was to identify the most up-regulated gene sets related to long-term physical activity vs. inactivity in skeletal muscle and adipose tissues and to obtain further information about their link with cardio-metabolic risk factors. We studied ten same-sex twin pairs (age range 50-74 years) who had been discordant for leisure-time physical activity for 30 years. The examinations included biopsies from m. vastus lateralis and abdominal subcutaneous adipose tissue. RNA was analyzed with the genome-wide Illumina Human WG-6 v3.0 Expression BeadChip. For pathway analysis we used Gene Set Enrichment Analysis utilizing active vs. inactive co-twin gene expression ratios. Our findings showed that among the physically active members of twin pairs, as compared to their inactive co-twins, gene expression in the muscle tissue samples was chronically up-regulated for the central pathways related to energy metabolism, including oxidative phosphorylation, lipid metabolism and supportive metabolic pathways. Up-regulation of these pathways was associated in particular with aerobic fitness and high HDL cholesterol levels. In fat tissue we found physical activity-associated increases in the expression of polyunsaturated fatty acid metabolism and branched-chain amino acid degradation gene sets both of which associated with decreased 'high-risk' ectopic body fat and plasma glucose levels. Consistent with other findings, plasma lipidomics analysis showed up-regulation of the triacylglycerols containing the polyunsaturated fatty acids. Our findings identified skeletal muscle and fat tissue pathways which are associated with the long-term physical activity and reduced cardio-metabolic disease risk, including increased aerobic fitness. In particular, improved skeletal muscle oxidative energy and lipid metabolism as well as changes in adipocyte function and redistribution of body fat are associated with reduced cardio-metabolic risk.

Purpose: Muscle hypertrophy is likely to result from the cumulative effects of repeated bouts of resistance exercise (RE) on postexercise molecular responses. Therefore, we determined muscle growth- and regeneration-related mRNA expression in response to a single RE bout both before and after a strength-training (ST) period. By means of this novel longitudinal setting, we examined whether postexercise gene expression at the transcriptional level is different in the trained and untrained state., Methods: Eleven untrained healthy older men and 11 controls (age 62.3 +/- 6.3 yr) volunteered as subjects. Muscle biopsies from the vastus lateralis muscle were taken at rest and 1 and 48 h after five sets of 10-repetition leg press RE both before and after 21 wk of supervised ST., Results: Myostatin and myogenin mRNA expression, determined by real-time RT-PCR, increased (P < 0.05) after ST. Conversely, the single RE bout decreased myostatin mRNA after ST, with the decrease showing a negative correlation (r = -0.65, P < 0.05) with the long-term increase in myostatin during ST. Furthermore, RE before ST increased myogenin mRNA (P < 0.05) and tended to increase after ST (P = 0.08). Myostatin receptor activin IIb mRNA levels were decreased at 1 h after RE in the pre-ST condition (P = 0.05) and also tended to decrease in the post-ST condition (P = 0.07). RE-induced downregulation in myostatin mRNA correlated with the ST-induced increase in total body muscle mass (r = -0.82, P = 0.002)., Conclusions: A single bout of RE in older men can downregulate the expression of myostatin receptor activin IIb mRNA. ST influences the response of myostatin to RE, as short-term RE-induced downregulation of myostatin was observed only after ST. The results also indicate that RE-induced alterations in myostatin mRNA expression may have a role in ST-induced muscle hypertrophy.

This study examined the effects of strength training and diet on serum basal hormone concentrations and muscle mass in aging women. Fifty-one women age 49 to 74 y were divided into two groups: strength training and nutritional counseling (n = 25), and strength training (n = 26). Both groups performed strength training twice a week for 21 wk. Nutritional counseling was given to attain sufficient energy and protein intake and recommended intake of fat and fiber. We found that the cross-sectional area of the quadriceps femoris increased by 9.5 +/- 4.1% in the nutritional counseling group versus 6.8 +/- 3.5% in the strength training only group after training (P < 0.052). Nutritional counseling evoked dietary changes such as increases in the proportion of energy from protein and the ratio of polyunsaturated and saturated fatty acids. Strength training increased testosterone and testosterone/sex hormone-binding globulin ratio after the first half of training, but these returned to baseline values at the end of the entire training period. Changes in serum basal hormone concentrations did not differ between the groups. Our results support the conclusion that nutritional counseling can contribute to the increase in the muscle cross-sectional area during prolonged strength training in aging women.

Progressive strength training can lead to substantial increases in maximal strength and mass of trained muscles, even in older women and men, but little information is available about the effects of strength training on functional capabilities and balance. Thus, the effects of 21 weeks of heavy resistance training--including lower loads performed with high movement velocities--twice a week on isometric maximal force (ISOmax) and force-time curve (force produced in 500 milliseconds, F0-500) and dynamic 1 repetition maximum (1RM) strength of the leg extensors, 10-m walking time (10WALK) and dynamic balance test (DYN.D) were investigated in 26 middle-aged (MI; 52.8 +/- 2.4 years) and 22 older women (O; 63.8 +/- 3.8 years). 1RM, ISOmax, and F0-500 increased significantly in MI by 28 +/- 10%, 20 +/- 19%, 31 +/- 34%, and in O by 27 +/- 8%, 20 +/- 16%, 18 +/- 45%, respectively. 10WALK (MI and O, p < 0.001) shortened and DYN.D improved (MI and O, p < 0.001). The present strength-training protocol led to large increases in maximal and explosive strength characteristics of leg extensors and in walking speed, as well to an improvement in the present dynamic balance test performance in both age groups. Although training-induced increase in explosive strength is an important factor for aging women, there are other factors that contribute to improvements in dynamic balance capacity. This study indicates that total body heavy resistance training, including explosive dynamic training, may be applied in rehabilitation or preventive exercise protocols in aging women to improve dynamic balance capabilities.

Acute and long-term hormonal and neuromuscular adaptations to hypertrophic strength training were studied in 13 recreationally strength-trained men. The experimental design comprised a 6-month hypertrophic strength-training period including 2 separate 3-month training periods with the crossover design, a training protocol of short rest (SR, 2 minutes) as compared with long rest (LR, 5 minutes) between the sets. Basal hormonal concentrations of serum total testosterone (T), free testosterone (FT), and cortisol (C), maximal isometric strength of the leg extensors, right leg 1 repetition maximum (1RM), dietary analysis, and muscle cross-sectional area (CSA) of the quadriceps femoris by magnetic resonance imaging (MRI) were measured at months 0, 3, and 6. The 2 hypertrophic training protocols used in training for the leg extensors (leg presses and squats with 10RM sets) were also examined in the laboratory conditions at months 0, 3, and 6. The exercise protocols were similar with regard to the total volume of work (loads x sets x reps), but differed with regard to the intensity and the length of rest between the sets (higher intensity and longer rest of 5 minutes vs. somewhat lower intensity but shorter rest of 2 minutes). Before and immediately after the protocols, maximal isometric force and electromyographic (EMG) activity of the leg extensors were measured and blood samples were drawn for determination of serum T, FT, C, and growth hormone (GH) concentrations and blood lactate. Both protocols before the experimental training period (month 0) led to large acute increases (p < 0.05-0.001) in serum T, FT, C , and GH concentrations, as well as to large acute decreases (p < 0.05-0.001) in maximal isometric force and EMG activity. However, no significant differences were observed between the protocols. Significant increases of 7% in maximal isometric force, 16% in the right leg 1RM, and 4% in the muscle CSA of the quadriceps femoris were observed during the 6-month strength-training period. However, both 3-month training periods performed with either the longer or the shorter rest periods between the sets resulted in similar gains in muscle mass and strength. No statistically significant changes were observed in basal hormone concentrations or in the profiles of acute hormonal responses during the entire 6-month experimental training period. The present study indicated that, within typical hypertrophic strength-training protocols used in the present study, the length of the recovery times between the sets (2 vs. 5 minutes) did not have an influence on the magnitude of acute hormonal and neuromuscular responses or long-term training adaptations in muscle strength and mass in previously strength-trained men.

The purpose of the present study was to examine genetic and environmental effects on maximal isometric handgrip, knee extension, and ankle plantar flexion strength. In addition, we wanted to investigate whether the strength of these three muscle groups shares a genetic component or whether the genetic effect is specific for each muscle group. Muscle strength was measured as part of the Finnish Twin Study on Aging in 97 monozygotic (MZ) and 102 dizygotic (DZ) female twin pairs, aged 63-76 yr. The MZ and DZ individuals did not differ from each other in age, body height, weight, or self-related health. The age-adjusted pairwise (intraclass) correlations of the MZ and DZ twins were, respectively, 0.462 and 0.242 in knee extension, 0.435 and 0.345 in handgrip, and 0.512 and 0.435 in ankle plantar flexion strength. The multivariate genetic analysis showed that handgrip and knee extension strength shared a genetic component, which accounted for 14% (95% confidence interval: 4-28%) of the variance in handgrip strength and 31% (95% confidence interval: 18-45%) in knee extension strength. The influence of genetic effects on ankle plantar flexion strength was minor and not significant. Furthermore, these three muscle groups had a nongenetic familial effect in common and nonshared environmental effects in common. The results suggested that muscle strength is under a genetic regulation, but also environmental effects have a significant role in explaining the variability in the muscle strength.

Hormonal and neuromuscular adaptations to strength training were studied in eight male strength athletes (SA) and eight non-strength athletes (NA). The experimental design comprised a 21-week strength-training period. Basal hormonal concentrations of serum total testosterone (T), free testosterone (FT) and cortisol (C) and maximal isometric strength, right leg 1 repetition maximum (RM) of the leg extensors were measured at weeks 0, 7, 14 and 21. Muscle cross-sectional area (CSA) of the quadriceps femoris was measured by magnetic resonance imaging (MRI) at weeks 0 and 21. In addition, the acute heavy resistance exercises (AHRE) (bilateral leg extension, five sets of ten RM, with a 2-min rest between sets) including blood samples for the determination of serum T, FT, C, and GH concentrations were assessed before and after the 21-week training. Significant increases of 20.9% in maximal force and of 5.6% in muscle CSA in NA during the 21-week strength training period were greater than those of 3.9% and -1.8% in SA, respectively. There were no significant changes in serum basal hormone concentrations during the 21-week experiment. AHRE led to significant acute decreases in isometric force and acute increases in serum hormones both at weeks 0 and 21. Basal T concentrations (mean of 0, 7, 14 and 21 weeks) and changes in isometric force after the 21-week period correlated with each other (r=0.84, P<0.01) in SA. The individual changes in the acute T responses between weeks 0 and 21 and the changes in muscle CSA during the 21-week training correlated with each other (r=0.76, P<0.05) in NA. The correlations between T and the changes in isometric strength and in muscle CSA suggest that both serum basal testosterone concentrations and training-induced changes in acute testosterone responses may be important factors for strength development and muscle hypertrophy.

Purpose: The aim of this study was to assess the effects of a resistance exercise session (RES) on free amino acid concentrations and protein synthesis and breakdown of the vastus lateralis (VL) muscle during recovery in male subjects., Methods: Both the exercise group (EG) and the control group (CG) consisted of six healthy physically active men. On the experiment day in fasting conditions, a stable isotopic tracer of L-[ring-2H(5)] phenylalanine was infused and EG started a heavy 50-min hypertrophic RES for lower extremities after 55 min of infusion. At the same time, CG was at rest. During recovery of 195 min after RES, several blood samples were drawn from the femoral artery (FA) and the femoral vein (FV) and muscle samples from the VL muscle. The enrichment was analyzed by GC/MS and leg muscle amino acid kinetics determined by three-pool compartment model between FA, FV, and VL., Results: During recovery at 60 min after RES, there was no difference in muscle protein synthesis or muscle protein breakdown between the groups, but at 195 min, both muscle protein synthesis (P < 0.05) and muscle protein breakdown (P < 0.05) were increased in EG compared with CG. The protein net balance was negative and similar in both groups. Simultaneously in serum concentrations, there was a decrease in leucine (P < 0.05) associated with an increase in aspartate (P < 0.05). Furthermore, the exercise-induced increase in alanine concentration decreased both in serum and muscle., Conclusion: In fasting conditions, protein net balance is negative and RES induces an increase in muscle protein synthesis and breakdown at 195 min but not yet at 60 min of recovery.

Eleven women (TRW; 64 +/- 4 yrs) and ten men (TRM; 65 +/- 5 yrs) participated in the strength/power training twice a week for 24 weeks. Basal concentrations of serum total and free testosterone, growth hormone (GH), dehydroepiandrosterone sulfate (DHEAS), cortisol and sex hormone binding globulin (SHBG) as well as acute responses of serum total and free testosterone, growth hormone (GH) were measured. Maximal 1RM strength in the squat, chair rise time and muscle fibre distribution and areas of type I and IIa and IIb of the vastus lateralis were also examined. 1RM squat increased in TRW by 26 (SD10)% (p < .001), and in TRM by 35 (7)% (p < .001) and chair rise time improved in both groups (p < .001). Fibre areas increased in type I, (p < .01), IIa (p < .01) and IIb (p < .01) in TRM and type I (p < .05) and IIa (p < .05) in TRW. The proportion of type IIa increased from 31% to 43% (p < .05) in TRW and that of type IIb decreased from 27% to 17% (p < .05) in TRW and from 25% to 17% (p < .05) in TRM. Individual concentrations of testosterone/cortisol ratios correlated (r = 0.63; p < .05) with the individual increases in 1RM strength in TRW. The exercise sessions resulted in acute increases in serum GH in both groups (p < .05) with a further increase (p < .01) up to 10 minutes post-loading in TRM at post-training.