Power training and postmenopausal hormone therapy affect transcriptional control of specific co-regulated gene clusters in skeletal muscle (original) (raw)
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Aging Cell, 2010
Aging is accompanied by inexorable loss of muscle tissue. One of the underlying causes for this is the massive change in the hormonal milieu of the body. The role of a female sex steroid -estrogen -in these processes is frequently neglected, although the rapid decline in its production coincides with a steep deterioration in muscle performance. We recruited 54-to 62-year-old monozygotic female twin pairs discordant for postmenopausal hormone replacement therapy (HRT, n = 11 pairs; HRT use 7.3 ± 3.7 years) from the Finnish Twin Cohort to investigate the association of long-term, estrogen-based HRT with skeletal muscle transcriptome. Pathway analysis of muscle transcript profiles revealed significant HRTinduced up-regulation of a biological process related to regulation of cell structure and down-regulation of processes concerning, for example, cell-matrix interactions, energy metabolism and utilization of nutrients (false discovery rate < 0.15). Lending clinical relevance to the findings, these processes explained a significant fraction of the differences observed in relative proportion of muscle within thigh and in muscle performance (R 2 = 0.180-0.257, P = 0.001-0.023). Although energy metabolism was affected through down-regulation of the transcripts related to succinate dehydrogenase complex in mitochondria, no differences were observed in mtDNA copy number or oxidative capacity per muscle cross section. In conclusion, long-term use of HRT was associated with subtle, but significant, differences in muscle transcript profiles. The better muscle composition and performance among the HRT users appeared to be orchestrated by improved regulatory actions on cytoskeleton, preservation of muscle quality via regulation of intramuscular extracellular matrix and a switch from glucose-oriented metabolism to utilization of fatty acids.
Aging Cell
Female middle age is characterized by a decline in skeletal muscle mass and performance, predisposing women to sarcopenia, functional limitations, and metabolic dysfunction as they age. Menopausal loss of ovarian function leading to low circulating level of 17b-estradiol has been suggested as a contributing factor to aging-related muscle deterioration. However, the underlying molecular mechanisms remain largely unknown and thus far androgens have been considered as a major anabolic hormone for skeletal muscle. We utilized muscle samples from 24 pre-and postmenopausal women to establish proteome-wide profiles, associated with the difference in age (30-34 years old vs. 54-62 years old), menopausal status (premenopausal vs. postmenopausal), and use of hormone replacement therapy (HRT; user vs. nonuser). None of the premenopausal women used hormonal medication while the postmenopausal women were monozygotic (MZ) cotwin pairs of whom the other sister was current HRT user or the other had never used HRT. Label-free proteomic analyses resulted in the quantification of 797 muscle proteins of which 145 proteins were for the first time associated with female aging using proteomics. Furthermore, we identified 17b-estradiol as a potential upstream regulator of the observed differences in muscle energy pathways. These findings pinpoint the underlying molecular mechanisms of the metabolic dysfunction accruing upon menopause, thus having implications for understanding the complex functional interactions between female reproductive hormones and health.
Experimental Gerontology, 2013
is an important post-translational regulatory mechanism mediated by O-GlcNAc transferase (OGT) and responsive to nutrients and stress. OGT attaches an O-GlcNAc moiety to proteins, while O-GlcNAcase (OGA) catalyzes O-GlcNAc removal. In skeletal muscle of experimental animals, prolonged increase in O-GlcNAcylation associates with age and muscle atrophy. Here we examined the effects of hormone replacement therapy (HRT) and power training (PT) on muscle OGT and OGA gene expression in postmenopausal women generally prone to age-related muscle weakness. In addition, the associations of OGT and OGA gene expressions with muscle phenotype were analyzed. Twenty-seven 50-57-year-old women participated in a yearlong randomized placebo-controlled trial: HRT (n = 10), PT (n = 8) and control (n = 9). OGT and OGA mRNA levels were measured from muscle samples obtained at baseline and after one year. Knee extensor muscle cross-sectional area (CSA), knee extension force, running speed and vertical jumping height were measured. During the yearlong intervention, HRT suppressed the aging-associated upregulation of OGT mRNA that occurred in the controls. The effects of PT were similar but weaker. HRT also tended to increase the OGA mRNA level compared to the controls. The change in the ratio of OGT to OGA gene expressions correlated negatively with the change in muscle CSA. Our results suggest that OGT and OGA gene expressions are associated with muscle size during the critical postmenopausal period. HRT and PT influence muscle OGT and OGA gene expression, which may be one of the mechanisms by which HRT and PT prevent aging-related loss of muscle mass.
Journal of Cachexia, Sarcopenia and Muscle
Background The andropause is associated with declines in serum testosterone (T), loss of muscle mass (sarcopenia), and frailty. Two major interventions purported to offset sarcopenia are anabolic steroid therapies and resistance exercise training (RET). Nonetheless, the efficacy and physiological and molecular impacts of T therapy adjuvant to short-term RET remain poorly defined. Methods Eighteen non-hypogonadal healthy older men, 65-75 years, were assigned in a random double-blinded fashion to receive, biweekly, either placebo (P, saline, n = 9) or T (Sustanon 250 mg, n = 9) injections over 6 week whole-body RET (three sets of 8-10 repetitions at 80% one-repetition maximum). Subjects underwent dual-energy X-ray absorptiometry, ultrasound of vastus lateralis (VL) muscle architecture, and knee extensor isometric muscle force tests; VL muscle biopsies were taken to quantify myogenic/anabolic gene expression, anabolic signalling, muscle protein synthesis (D 2 O), and breakdown (extrapolated). Results Testosterone adjuvant to RET augmented total fat-free mass (P=0.007), legs fat-free mass (P=0.02), and appendicular fat-free mass (P=0.001) gains while decreasing total fat mass (P=0.02). Augmentations in VL muscle thickness, fascicle length, and quadriceps cross-section area with RET occured to a greater extent in T (P < 0.05). Sum strength (P=0.0009) and maximal voluntary contract (e.g. knee extension at 70°) (P=0.002) increased significantly more in the T group. Mechanistically, both muscle protein synthesis rates (T: 2.13 ± 0.21%•day À1 vs. P: 1.34 ± 0.13%•day À1 , P=0.0009) and absolute breakdown rates (T: 140.2 ± 15.8 g•day À1 vs. P: 90.2 ± 11.7 g•day À1 , P=0.02) were elevated with T therapy, which led to higher net turnover and protein accretion in the T group (T: 8.3 ± 1.4 g•day À1 vs. P: 1.9 ± 1.2 g•day À1 , P=0.004). Increases in ribosomal biogenesis (RNA:DNA ratio); mRNA expression relating to T metabolism (androgen receptor: 1.4-fold; Srd5a1: 1.6-fold; AKR1C3: 2.1-fold; and HSD17β3: twofold); insulin-like growth factor (IGF)-1 signalling [IGF-1Ea (3.5-fold) and IGF-1Ec (three-fold)] and myogenic regulatory factors; and the activity of anabolic signalling (e.g. mTOR, AKT, and RPS6; P < 0.05) were all up-regulated with T therapy. Only T up-regulated mitochondrial citrate synthase activity (P=0.03) and transcription factor A (1.41 ± 0.2-fold, P=0.0002), in addition to peroxisome proliferator-activated receptor-γ co-activator 1-α mRNA (1.19 ± 0.21-fold, P=0.037). Conclusions Administration of T adjuvant to RET enhanced skeletal muscle mass and performance, while up-regulating myogenic gene programming, myocellular translational efficiency and capacity, collectively resulting in higher protein turnover, and net protein accretion. T coupled with RET is an effective short-term intervention to improve muscle mass/function in older non-hypogonadal men.
Progesterone increases skeletal muscle mitochondrial H2O2 emission in nonmenopausal women
American Journal of …, 2011
The luteal phase of the female menstrual cycle is associated with both 1) elevated serum progesterone (P4) and estradiol (E2), and 2) reduced insulin sensitivity. Recently, we demonstrated a link between skeletal muscle mitochondrial H2O2 emission (mEH2O2) and insulin resistance. To determine whether serum levels of P4 and/or E2 are related to mitochondrial function, mEH2O2 and respiratory O2 flux (Jo2) were measured in permeabilized myofibers from insulin-sensitive (IS, n = 24) and -resistant (IR, n = 8) nonmenopausal women (IR = HOMA-IR > 3.6). Succinate-supported mEH2O2 was more than 50% greater in the IR vs. IS women (P < 0.05). Interestingly, serum P4 correlated positively with succinate-supported mEH2O2 (r = 0. 53, P < 0.01). To determine whether P4 or E2 directly affect mitochondrial function, saponin-permeabilized vastus lateralis myofibers biopsied from five nonmenopausal women in the early follicular phase were incubated in P4 (60 nM), E2 (1.4 nM), or both. P4 alone inhibited state 3 Jo2, supported by multisubstrate combination (P < 0.01). However, E2 alone or in combination with P4 had no effect on Jo2. In contrast, during state 4 respiration, supported by succinate and glycerophosphate, mEH2O2 was increased with P4 alone or in combination with E2 (P < 0.01). The results suggest that 1) P4 increases mEH2O2 with or without E2; 2) P4 alone inhibits Jo2 but not when E2 is present; and 3) P4 is related to the mEH2O2 previously linked to skeletal muscle insulin resistance.
Hormone therapy attenuates exercise-induced skeletal muscle damage in postmenopausal women
Journal of Applied Physiology, 2009
Hormone therapy attenuates exercise-induced skeletal muscle damage in postmenopausal women. mone therapy (HT) is a potential treatment to relieve symptoms of menopause and prevent the onset of disease such as osteoporosis in postmenopausal women. We evaluated changes in markers of exercise-induced skeletal muscle damage and inflammation [serum creatine kinase (CK), serum lactate dehydrogenase (LDH), and skeletal muscle mRNA expression of IL-6, IL-8, IL-15, and TNF-␣] in postmenopausal women after a high-intensity resistance exercise bout. Fourteen postmenopausal women were divided into two groups: women not using HT (control; n ϭ 6, 59 Ϯ 4 yr, 63 Ϯ 17 kg) and women using traditional HT (HT; n ϭ 8, 59 Ϯ 4 yr, 89 Ϯ 24 kg). Both groups performed 10 sets of 10 maximal eccentric repetitions of single-leg extension on the Cybex dynamometer at 60°/s with 20-s rest periods between sets. Muscle biopsies of the vastus lateralis were obtained from the exercised leg at baseline and 4 h after the exercise bout. Gene expression was determined by RT-PCR for IL-6, IL-8, IL-15, and TNF-␣. Blood draws were performed at baseline and 3 days after exercise to measure CK and LDH. Independent t-tests were performed to test group differences (control vs. HT). A probability level of P Յ 0.05 was used to determine statistical significance. We observed significantly greater changes in mRNA expression of IL-6, IL-8, IL-15, and TNF-␣ (P Յ 0.01) in the control group compared with the HT group after the exercise bout. CK and LDH levels were significantly greater after exercise (P Յ 0.01) in the control group. Postmenopausal women not using HT experienced greater muscle damage after maximal eccentric exercise, indicating a possible protective effect of HT against exercise-induced skeletal muscle damage. creatine kinase; lactate dehydrogenase; tumor necrosis factor-␣
Resistance exercise reverses aging in human skeletal muscle
2007
Human aging is associated with skeletal muscle atrophy and functional impairment (sarcopenia). Multiple lines of evidence suggest that mitochondrial dysfunction is a major contributor to sarcopenia. We evaluated whether healthy aging was associated with a transcriptional profile reflecting mitochondrial impairment and whether resistance exercise could reverse this signature to that approximating a younger physiological age. Skeletal muscle biopsies from healthy older (N = 25) and younger (N = 26) adult men and women were compared using gene expression profiling, and a subset of these were related to measurements of muscle strength. 14 of the older adults had muscle samples taken before and after a six-month resistance exercise-training program. Before exercise training, older adults were 59% weaker than younger, but after six months of training in older adults, strength improved significantly (P,0.001) such that they were only 38% lower than young adults. As a consequence of age, we found 596 genes differentially expressed using a false discovery rate cutoff of 5%. Prior to the exercise training, the transcriptome profile showed a dramatic enrichment of genes associated with mitochondrial function with age. However, following exercise training the transcriptional signature of aging was markedly reversed back to that of younger levels for most genes that were affected by both age and exercise. We conclude that healthy older adults show evidence of mitochondrial impairment and muscle weakness, but that this can be partially reversed at the phenotypic level, and substantially reversed at the transcriptome level, following six months of resistance exercise training.
Scientific Reports
Previous studies have highlighted the positive effects of Estradiol (E2) replacement therapy and physical exercise on skeletal muscle during menopause. However, the comparison effects of exercise training (ET) and estradiol replacement therapy during menopause on skeletal muscle have not been investigated to date. This study aimed to compare the effects of endurance exercise training versus E2 replacement therapy on mitochondrial density, redox status, and inflammatory biomarkers in the skeletal muscle of ovariectomized rats. Thirty female Wistar rats (12-week-old) were randomly assigned into three groups: Untrained ovariectomized rats (UN-OVX, n = 10); untrained ovariectomized rats treated with estradiol replacement therapy (E2-OVX); and, trained ovariectomized rats (TR-OVX). After ovariectomy, the E2-OVX rats were treated subcutaneously with E2 (implanted Silastic® capsule containing 360 μg of 17β-estradiol/mL) while the TR-OVX group performed an exercise training protocol (50–70%...
Thyroid Hormone and Estrogen Regulate Exercise-Induced Growth Hormone Release
PLOS ONE, 2015
DP. Role of estrogen on skeletal muscle mitochondrial function in ovariectomized rats: a time course study in different fiber types. Postmenopausal women are prone to develop obesity and insulin resistance, which might be related to skeletal muscle mitochondrial dysfunction. In a rat model of ovariectomy (OVX), skeletal muscle mitochondrial function was examined at short-and long-term periods after castration. Mitochondrial parameters in the soleus and white gastrocnemius muscle fibers were analyzed. Three weeks after surgery, there were no differences in coupled mitochondrial respiration (ATP synthesis) with pyruvate, malate, and succinate; proton leak respiration; or mitochondrial reactive oxygen species production. However, after 3 wk of OVX, the soleus and white gastrocnemius muscles of the OVX animals showed a lower use of palmitoyl-carnitine and glycerol-phosphate substrates, respectively, and decreased peroxisome proliferator-activated receptor-␥ coactivator-1␣ expression. Estrogen replacement reverted all of these phenotypes. Eight weeks after OVX, ATP synthesis was lower in the soleus and white gastrocnemius muscles of the OVX animals than in the sham-operated and estrogen-treated animals; however, when normalized by citrate synthase activity, these differences disappeared, indicating a lower muscle mitochondria content. No differences were observed in the proton leak parameter. Mitochondrial alterations did not impair the treadmill exercise capacity of the OVX animals. However, blood lactate levels in the OVX animals were higher after the physical test, indicating a compensatory extramitochondrial ATP synthesis system, but this phenotype was reverted by estrogen replacement. These results suggest early mitochondrial dysfunction related to lipid substrate use, which could be associated with the development of the overweight phenotype of ovariectomized animals. mitochondria; skeletal muscle; ovariectomy; rats ESTROGEN DEFICIENCY (24, or the absence of estrogen receptor ␣ (ER-␣) (19) can promote an increase in body mass adiposity, at least in part, due to higher energy intake, as detected previously in rats (48). However, pair-fed, estrogendeficient animals also became overweight (14), suggesting that changes in energy metabolism might also take place in estrogen-deficient animals (50).
Physiological Genomics, 2011
Oosterhof R, Ith M, Trepp R, Christ E, Flück M. Regulation of whole body energy homeostasis with growth hormone replacement therapy and endurance exercise. We hypothesized that network analysis is useful to expose coordination between whole body and myocellular levels of energy metabolism and can identify entities that underlie skeletal muscle's contribution to growth hormone-stimulated lipid handling and metabolic fitness. We assessed 112 metabolic parameters characterizing metabolic rate and substrate handling in tibialis anterior muscle and vascular compartment at rest, after a meal and exercise with growth hormone replacement therapy (GH-RT) of hypopituitary patients (n ϭ 11). The topology of linear relationships (| r | Ն 0.7, P Յ 0.01) and mutual dependencies exposed the organization of metabolic relationships in three entities reflecting basal and exercise-induced metabolic rate, triglyceride handling, and substrate utilization in the pre-and postprandial state, respectively. GH-RT improved aerobic performance (ϩ5%), lean-to-fat mass (ϩ19%), and muscle area of tibialis anterior (ϩ2%) but did not alter its mitochondrial and capillary content. Concomitantly, connectivity was established between myocellular parameters of mitochondrial lipid metabolism and meal-induced triglyceride handling in serum. This was mediated via the recruitment of transcripts of muscle lipid mobilization (LIPE, FABP3, and FABP4) and fatty acid-sensitive transcription factors (PPARA, PPARG) to the metabolic network. The interdependence of gene regulatory elements of muscle lipid metabolism reflected the norm in healthy subjects (n ϭ 12) and distinguished the regulation of the mitochondrial respiration factor COX1 by GH and endurance exercise. Our observations validate the use of network analysis for systems medicine and highlight the notion that an improved stochiometry between muscle and whole body lipid metabolism, rather than alterations of single bottlenecks, contributes to GH-driven elevations in metabolic fitness.