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Activity of MSTN and IL-6 promoter constructs in 3T3-L1 adipocytes and C2C12 muscle cells. A: MSTN promoter activity in undifferentiated preadipocytes and 4-day-differentiated adipocytes. Activity was slightly higher in adipocytes than in preadipocytes (pre-ad). B: IL-6 promoter activity in 3T3-L1 preadipocytes and 4-day-differentiated adipocytes. IL-6 promoter activity was significantly lower in adipocytes than in pre-ad. C: MSTN and IL-6 promoter activity in C2C12 myotubes. MSTN promoter activity was 25-fold higher in C2C12 myotubes than in 3T3-L1 adipocytes. D: effects of cotransfection of adipogenic transcription factors STAT5b, CCAAT/ enhancer-binding protein-(C/EBP), peroxisome proliferator-activated receptor-(PPAR), and sterol response element-binding protein-1c (SREBP-1c) on MSTN promoter activity in 3T3-L1 adipocytes. C/EBP, PPAR, and SREBP-1c cotransfection resulted in an 7-to 20-fold increase in MSTN promoter activity compared with transfection with a cytomegalovirus-green fluorescent protein control. *Significantly different from GFP transfected, P 0.05.
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Myostatin (MSTN) is a secreted growth inhibitor expressed in muscle and adipose. We sought to determine whether expression of MSTN, its receptor activin RIIb (ActRIIb), or its binding protein follistatin-like-3 (FSTL3) are altered in subcutaneous or visceral adipose or in skeletal muscle in response to obesity. MSTN and ActRIIb mRNA levels were low...
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... with the mRNA data, activity of a 1.2-kb mouse MSTN promoter construct was very low but detectable in 3T3-L1 cells (Fig. 8A) and was similar in magnitude in C 2 C 12 myoblasts (Fig. 8C). However, MSTN promoter activity was unaffected by 4 days of differentiation in 3T3-L1 adipocytes (Fig. 8A) but showed significant upregulation in C 2 C 12 myo- tubes (Fig. 8C), as has been shown previously (22). In contrast, a human IL-6 promoter construct showed extremely ...
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... with the mRNA data, activity of a 1.2-kb mouse MSTN promoter construct was very low but detectable in 3T3-L1 cells (Fig. 8A) and was similar in magnitude in C 2 C 12 myoblasts (Fig. 8C). However, MSTN promoter activity was unaffected by 4 days of differentiation in 3T3-L1 adipocytes (Fig. 8A) but showed significant upregulation in C 2 C 12 myo- tubes (Fig. 8C), as has been shown previously (22). In contrast, a human IL-6 promoter construct showed extremely high levels in preadipocytes but decreased substantially upon ...
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... with the mRNA data, activity of a 1.2-kb mouse MSTN promoter construct was very low but detectable in 3T3-L1 cells (Fig. 8A) and was similar in magnitude in C 2 C 12 myoblasts (Fig. 8C). However, MSTN promoter activity was unaffected by 4 days of differentiation in 3T3-L1 adipocytes (Fig. 8A) but showed significant upregulation in C 2 C 12 myo- tubes (Fig. 8C), as has been shown previously (22). In contrast, a human IL-6 promoter construct showed extremely high levels in preadipocytes but decreased substantially upon differentia- tion (Fig. 8B). Finally, cotransfection of the mouse MSTN promoter construct with expression ...
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... the mRNA data, activity of a 1.2-kb mouse MSTN promoter construct was very low but detectable in 3T3-L1 cells (Fig. 8A) and was similar in magnitude in C 2 C 12 myoblasts (Fig. 8C). However, MSTN promoter activity was unaffected by 4 days of differentiation in 3T3-L1 adipocytes (Fig. 8A) but showed significant upregulation in C 2 C 12 myo- tubes (Fig. 8C), as has been shown previously (22). In contrast, a human IL-6 promoter construct showed extremely high levels in preadipocytes but decreased substantially upon differentia- tion (Fig. 8B). Finally, cotransfection of the mouse MSTN promoter construct with expression constructs for C/EBP, PPAR, and SREBP-1c resulted in a significant ...
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... MSTN promoter activity was unaffected by 4 days of differentiation in 3T3-L1 adipocytes (Fig. 8A) but showed significant upregulation in C 2 C 12 myo- tubes (Fig. 8C), as has been shown previously (22). In contrast, a human IL-6 promoter construct showed extremely high levels in preadipocytes but decreased substantially upon differentia- tion (Fig. 8B). Finally, cotransfection of the mouse MSTN promoter construct with expression constructs for C/EBP, PPAR, and SREBP-1c resulted in a significant increase in MSTN promoter activity in 3T3-L1 cells compared with co- transfection with a cytomegalovirus-green fluorescent protein control, whereas STAT5b had no effect (Fig. 8D). Together ...
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... upon differentia- tion (Fig. 8B). Finally, cotransfection of the mouse MSTN promoter construct with expression constructs for C/EBP, PPAR, and SREBP-1c resulted in a significant increase in MSTN promoter activity in 3T3-L1 cells compared with co- transfection with a cytomegalovirus-green fluorescent protein control, whereas STAT5b had no effect (Fig. 8D). Together these data suggest that MSTN gene expression in cultured Fig. 4. Effects of leptin-deficient obesity on expression of the MSTN-signaling system in TA and soleus (SOL) mus- cle. A: TA and SOL muscle mass in wild-type and ob/ob mice. TA mass was significantly lower in ob/ob (black bars) compared with wild-type mice (open ...
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... to determine whether MSTN tran- scription is responsive to proadipogenic transcription factor signaling in the adipogenic 3T3-L1 line. MSTN mRNA could be detected only at very low levels in 3T3-L1 preadipocytes or adipocytes (data not shown), but an MSTN promoter-reporter construct showed activity comparable with that seen in C 2 C 12 myoblasts (Fig. 8, A and C), and we therefore used this as a sensor for MSTN transcription. Activity of the MSTN pro- moter construct was not significantly altered in 4-day-differ- entiated 3T3-L1 adipocytes compared with preadipocytes (Fig. 8A); this was in contrast to the expression pattern of the MSTN promoter construct in C 2 C 12 cells, which showed a ...
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... (data not shown), but an MSTN promoter-reporter construct showed activity comparable with that seen in C 2 C 12 myoblasts (Fig. 8, A and C), and we therefore used this as a sensor for MSTN transcription. Activity of the MSTN pro- moter construct was not significantly altered in 4-day-differ- entiated 3T3-L1 adipocytes compared with preadipocytes (Fig. 8A); this was in contrast to the expression pattern of the MSTN promoter construct in C 2 C 12 cells, which showed a dramatic induction upon differentiation (Fig. 8C), and to the expression pattern of an IL-6 promoter construct, which showed very high activity in preadipocytes and much lower activity in differen- tiated adipocytes (Fig. ...
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... this as a sensor for MSTN transcription. Activity of the MSTN pro- moter construct was not significantly altered in 4-day-differ- entiated 3T3-L1 adipocytes compared with preadipocytes (Fig. 8A); this was in contrast to the expression pattern of the MSTN promoter construct in C 2 C 12 cells, which showed a dramatic induction upon differentiation (Fig. 8C), and to the expression pattern of an IL-6 promoter construct, which showed very high activity in preadipocytes and much lower activity in differen- tiated adipocytes (Fig. 8B). In addition, the MSTN construct was activated approximately seven-to 20-fold by cotransfec- tion with the adipogenic transcription factors C/EBP, PPAR, and ...
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... (Fig. 8A); this was in contrast to the expression pattern of the MSTN promoter construct in C 2 C 12 cells, which showed a dramatic induction upon differentiation (Fig. 8C), and to the expression pattern of an IL-6 promoter construct, which showed very high activity in preadipocytes and much lower activity in differen- tiated adipocytes (Fig. 8B). In addition, the MSTN construct was activated approximately seven-to 20-fold by cotransfec- tion with the adipogenic transcription factors C/EBP, PPAR, and SREBP-1c but not by the adipogenic coactivator STAT5b (Fig. 8D). Expression of these transcription factors has been shown to be upregulated during conditions favoring adipose ...
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... promoter construct, which showed very high activity in preadipocytes and much lower activity in differen- tiated adipocytes (Fig. 8B). In addition, the MSTN construct was activated approximately seven-to 20-fold by cotransfec- tion with the adipogenic transcription factors C/EBP, PPAR, and SREBP-1c but not by the adipogenic coactivator STAT5b (Fig. 8D). Expression of these transcription factors has been shown to be upregulated during conditions favoring adipose tissue growth and hypertrophy (12,26,32,35,40,41). The mouse MSTN upstream promoter region contains consensus- binding sites for STAT, PPAR, and C/EBP transcription fac- tors but was unresponsive to STAT5b cotransfection. ...
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Obesity, one of the major public health problems worldwide, has attracted increasing attention. Ginsenoside Rb1 is the most abundant active component of Panax ginseng C.A.Mey (Araliaceae) and is reported to have beneficial effects on obesity and diabetes. However, the mechanisms by which Rb1 regulates obesity remain to be explored.
Objecti...
Citations
... Myostatin, also called growth differentiation factor 8 (GDF-8), is a myokine that belongs to the transforming growth factor (TGF)-β superfamily. Since its discovery, myostatin has been recognized as a potential mediator of muscle atrophy in various pathological conditions, including obesity [10] and T2DM [11]. Myostatin is, in fact, one of the primary negative regulators of muscle growth [12]. ...
Skeletal muscle plays a critical role in metabolic diseases, such as obesity and type 2 diabetes mellitus (T2DM). Muscle atrophy, characterized by a decrease in muscle mass and function, occurs due to an imbalance between the rates of muscle protein synthesis and degradation. This study aimed to investigate the molecular mechanisms that lead to muscle atrophy in obese and T2DM mouse models. Additionally, the effect of nerve growth factor (NGF) on the protein synthesis and degradation pathways was examined. Male mice were divided into three groups: a control group that was fed a standard chow diet, and two experimental groups that were fed a Western diet. After 8 weeks, the diabetic group was injected with streptozotocin to induce T2DM. Each group was then further divided into NGF-treated or non-treated control group. In the gastrocnemius muscles of the Western diet group, increased expressions of myostatin, autophagy markers, and ubiquitin ligases were observed. Skeletal muscle tissue morphology indicated signs of muscle atrophy in both obese and diabetic mice. The NGF-treated group showed a prominent decrease in the protein levels of myostatin and autophagy markers. Furthermore, the NGF-treated group showed an increased Cyclin D1 level. Western diet-induced obesity and T2DM may be linked to muscle atrophy through upregulation of myostatin and subsequent increase in the ubiquitin and autophagy systems. Moreover, NGF treatment may improve muscle protein synthesis and cell cycling.
... The liver plays a central role in the synthesis and metabolism of bile acids and lipids. MSTN has been shown to regulate key hepatic enzymes involved in lipid and bile acid metabolism, such as SREBP-1 and FXR [51,52]. The MSTN mutation could affect the activity or expression of these enzymes, thereby influencing bile acid and lipid homeostasis. ...
Myostatin (MSTN) is a negative regulator of skeletal muscle genesis during development. MSTN mutation leads to increased lean meat production and reduced fat deposition in livestock. However, the mechanism by which MSTN promotes myogenesis by regulating metabolism is not clear. In this study, we compared the metabolomics of the livers of wild-type (WT) and MSTN mutation cattle (MT), and found changes in the content and proportion of fatty acids and bile acids in MT cattle. The differential metabolites were enriched in sterol synthesis and primary bile acid synthesis. We further analyzed the expression of genes involved in the regulation of lipid and bile acid metabolism, and found that the loss of MSTN may alter lipid synthesis and bile acid metabolism. This study provides new basic data for MSTN mutations in beef cattle breeding.
... Cord blood myostatin concentrations were similar in GDM vs. controls. Skeletal muscle is the dominant source of circulating myostatin (1); skeletal muscle-specific expression of myostatin is about 50-100 fold higher than adipose tissue-specific expression (28). Whether GDM affects skeletal muscle mass remains controversial; similar or lower lean mass has been reported in the neonates of GDM vs. controls (29,30). ...
Introduction:
Myostatin is a member of the transforming growth factor β superfamily, and is mainly secreted from skeletal muscle. Animal studies have demonstrated that deficiency in myostatin promotes muscle growth and protects against insulin resistance. In humans, gestational diabetes mellitus (GDM) affects fetal insulin sensitivity. Females are more insulin resistant and weigh less than males at birth. We sought to assess whether cord blood myostatin concentrations vary by GDM and fetal sex, and the associations with fetal growth factors.
Methods:
In a study of 44 GDM and 66 euglycemic mother-newborn dyads, myostatin, insulin, proinsulin, insulin-like growth factor (IGF)-1, IGF-2 and testosterone were measured in cord blood samples.
Results:
Cord blood myostatin concentrations were similar in GDM vs. euglycemic pregnancies (mean ± SD: 5.5 ± 1.4 vs. 5.8 ± 1.4 ng/mL, P=0.28), and were higher in males vs. females (6.1 ± 1.6 vs. 5.3 ± 1.0 ng/mL, P=0.006). Adjusting for gestational age, myostatin was negatively correlated with IGF-2 (r=-0.23, P=0.02), but not correlated with IGF-1 (P=0.60) or birth weight (P=0.23). Myostatin was strongly correlated with testosterone in males (r=0.56, P<0.001), but not in females (r=-0.08, P=0.58) (test for difference in r, P<0.001). Testosterone concentrations were higher in males vs. females (9.5 ± 6.4 vs. 7.1 ± 4.0 nmol/L, P=0.017), and could explain 30.0% (P=0.039) of sex differences in myostatin concentrations.
Discussion:
The study is the first to demonstrate that GDM does not impact cord blood myostatin concentration, but fetal sex does. The higher myostatin concentrations in males appear to be partly mediated by higher testosterone concentrations. These findings shed novel insight on developmental sex differences in insulin sensitivity regulation relevant molecules.
... To examine the tissue expression profile of FSTL3, we first analyzed a published available human tissue proteomics database [20] and found that FSTL3 was highly expressed in adipose tissue (Supporting Information Figure S1). Higher FSTL3 expression in adipose tissue has also been confirmed by a previous study [21]. Then we performed high-throughput transcriptome sequencing of paired SAT and VAT of 236 participants (including 65 normal-weight individuals and 171 individuals with overweight or obesity) to further identify the FSTL3 expression profile. ...
Objective:
This study aimed to investigate the expression of follistatin-like 3 (FSTL3) in adipose tissue in individuals with overweight or obesity and to explore the role of FSTL3 in human adipocytes, as well as the relationship between serum FSTL3 levels and fat distribution and inflammation.
Methods:
This study enrolled 236 individuals (171 with overweight or obesity; aged 18-67 years). Bulk transcriptome sequencing was performed on subcutaneous and visceral adipose tissue. The function of FSTL3 was studied in human adipocytes. Serum FSTL3 levels were measured using enzyme-linked immunosorbent assay.
Results:
Adipose FTSL3 expression was higher in individuals with overweight or obesity than in individuals with normal weight. FSTL3 was mainly expressed in mature adipocytes and stimulated by tumor necrosis factor alpha (TNFα). FSTL3 suppressed inflammatory responses in human adipocytes, whereas FSTL3 knockdown promoted inflammatory responses. Serum FSTL3 levels were correlated with adipose FTSL3 expression and obesity-related indicators (all p < 0.05). Multiple linear regression analysis showed that serum FSTL3 levels were independently associated with the visceral fat area and serum TNFα levels (both p < 0.05).
Conclusions:
FSTL3 was highly expressed in adipose tissue in individuals with overweight or obesity and could suppress adipocyte inflammation. Serum FSTL3 levels might be considered as a biomarker of visceral obesity and inflammation.
... Myostatin is solely expressed in skeletal muscle during embryogenesis to control the differentiation and proliferation of the myoblasts (McPherron et al., 1997). However, in the adult stage, it is expressed not only in skeletal muscle but also in other tissues like the heart, adipose tissue, and mammary gland (McPherron et al., 1997;Ji et al., 1998;Sharma et al., 1999;Morissette et al., 2006;Shyu et al., 2006;Allen et al., 2008). In turkey satellite cells, MSTN is a strong negative regulator for skeletal muscle growth, differentiation, and proliferation (McPherron et al., 1997;McFarland et al., 2006). ...
Background: Muscle development, egg production, and plumage colors are different between native and broiler chickens. The study was designed to investigate why improved Aseel (PD4) is colorful, stronger, and grew slowly compared with the control broiler (CB).
Methods: A microarray was conducted using the 7th-day embryo (7EB) and 18th-day thigh muscle (18TM) of improved Aseel and broiler, respectively. Also, we have selected 24 Gallus gallus candidate reference genes from NCBI, and total RNA was isolated from the broiler, improved Aseel embryo tissues, and their expression profiles were studied by real-time quantitative PCR (qPCR). Furthermore, microarray data were validated with qPCR using improved Aseel and broiler embryo tissues.
Results: In the differential transcripts screening, all the transcripts obtained by microarray of slow and fast growth groups were screened by fold change ≥ 1 and false discovery rate (FDR) ≤ 0.05. In total, 8,069 transcripts were differentially expressed between the 7EB and 18TM of PD4 compared to the CB. A further analysis showed that a high number of transcripts are differentially regulated in the 7EB of PD4 (6,896) and fewer transcripts are differentially regulated (1,173) in the 18TM of PD4 compared to the CB. On the 7th⁻ and 18th-day PD4 embryos, 3,890, 3,006, 745, and 428 transcripts were up- and downregulated, respectively. The commonly up- and downregulated transcripts are 91 and 44 between the 7th- and 18th-day of embryos. In addition, the best housekeeping gene was identified. Furthermore, we validated the differentially expressed genes (DEGs) related to muscle growth, myostatin signaling and development, and fatty acid metabolism genes in PD4 and CB embryo tissues by qPCR, and the results correlated with microarray expression data.
Conclusion: Our study identified DEGs that regulate the myostatin signaling and differentiation pathway; glycolysis and gluconeogenesis; fatty acid metabolism; Jak-STAT, mTOR, and TGF-β signaling pathways; tryptophan metabolism; and PI3K-Akt signaling pathways in PD4. The results revealed that the gene expression architecture is present in the improved Aseel exhibiting embryo growth that will help improve muscle development, differentiation, egg production, protein synthesis, and plumage formation in PD4 native chickens. Our findings may be used as a model for improving the growth in Aseel as well as optimizing the growth in the broiler.
... Myostatin is a secreted growth and differentiation factor that belongs to the TGF-β superfamily [34] and has been clearly defined as a negative regulator of muscle and bone [35,36]. Myostatin elicits osteoclastogenesis and reduces bone formation [35,37]. ...
... Myostatin is a secreted growth and differentiation factor that belongs to the TGF-β superfamily [34] and has been clearly defined as a negative regulator of muscle and bone [35,36]. Myostatin elicits osteoclastogenesis and reduces bone formation [35,37]. Suppressing myostatin in the osteogenic differentiation of bone marrow stem cells induces the expression of osteogenic growth factors, such as insulin like growth factor-1 (IGF-1), leading to increasing osteoblast proliferation and accelerating bone formation [37]. ...
Bone has long been considered as a silent organ that provides a reservoir of calcium and phosphorus, traditionally. Recently, further study of bone has revealed additional functions as an endocrine organ connecting systemic organs of the whole body. Communication between bone and other organs participates in most physiological and pathological events and is responsible for the maintenance of homeostasis. Here, we present an overview of the crosstalk between bone and other organs. Furthermore, we describe the factors mediating the crosstalk and review the mechanisms in the development of potential associated diseases. These connections shed new light on the pathogenesis of systemic diseases and provide novel potential targets for the treatment of systemic diseases.
... Studies have explored the impact of MSTN on insulin resistance, and several studies conducted using mouse models have provided evidence that the absence of MSTN has significant effects on metabolism, that is, it improves insulin sensitivity and reduces obesity (Amor et al., 2019). Many studies have suggested that MSTN has a substantial impact on metabolism and may contribute to the development of obesity and diabetes (Allen et al., 2008;Allen et al., 2011). MSTN protein secretion was higher from the cultured myotubes of obese insulin-resistant subjects. ...
Myostatin (MSTN) is a well-reported negative regulator of muscle growth and a member of the transforming growth factor (TGF) family. MSTN has important functions in skeletal muscle (SM), and its crucial involvement in several disorders has made it an important therapeutic target. Several strategies based on the use of natural compounds to inhibitory peptides are being used to inhibit the activity of MSTN. This review delivers an overview of the current state of knowledge about SM and myogenesis with particular emphasis on the structural characteristics and regulatory functions of MSTN during myogenesis and its involvements in various muscle related disorders. In addition, we review the diverse approaches used to inhibit the activity of MSTN, especially in silico approaches to the screening of natural compounds and the design of novel short peptides derived from proteins that typically interact with MSTN.
... Heart, Liver, Adipocytes ↑ Glucose uptake [120] ↑ β-oxidation [123,192] Myostatin Adipose tissue, Liver, Bone, Muscle ↓Decrease glucose uptake and insulin sensitivity [193][194][195] Osteoglycin Muscle, Bone ↑ Glucose metabolism [196] ↑ Fatty acid oxidation [197] SPARC Adipose tissue, Muscle ↑ Glucose tolerance [76] inhibits adipogenesis [198] ...
The skeletal muscle is the largest organ in the body and secretes circulating factors, including myokines, which are involved in various cellular signaling processes. Skeletal muscle is vital for metabolism and physiology and plays a crucial role in insulin-mediated glucose disposal. Myokines have autocrine, paracrine, and endocrine functions, serving as critical regulators of myogenic differentiation, fiber-type switching, and maintaining muscle mass. Myokines have profound effects on energy metabolism and inflammation, contributing to the pathophysiology of type 2 diabetes (T2D) and other metabolic diseases. Myokines have been shown to increase insulin sensitivity, thereby improving glucose disposal and regulating glucose and lipid metabolism. Many myokines have now been identified, and research on myokine signaling mechanisms and functions is rapidly emerging. This review summarizes the current state of the field regarding the role of myokines in tissue cross-talk, including their molecular mechanisms, and their potential as therapeutic targets for T2D.
... The relationship between elevated myostatin and obesity has been demonstrated in both rodent and human studies. For example, myostatin mRNA is increased in both skeletal muscle and adipose tissues in wild type mice fed a high fat diet and genetically obese mice [24]. Increased circulating and muscle myostatin concentrations have been reported in adults with extreme obesity (i.e. ...
Abstract Background Elevated concentrations of myostatin inhibit muscle growth, function and strength. Myostatin is a mediator of sarcopenia and is associated with insulin resistance. For this study we tested the response of a calorie-restricted Dietary Approaches to Stop Hypertension (DASH) diet on changes in myostatin, follistatin, and mystatin:follistatin ratio levels after 12 weeks in comparison to basline in adults aged 65 years and older. Furthermore we evaluated correlations between changes in myostatin, body composition and cardiometabolic biomarkers in this cohort of older adults. Methods This was a controlled-feeding diet intervention study in which females (n = 17) and males (n = 11) aged 65 years and older consumed either 85 g (n = 15) or 170 g (n = 13) of fresh lean beef within a standardized DASH diet for 12-weeks. Myostatin and follistatin concentrations were measured from fasted blood samples collected at 5 timepoints throughout the 12-week feeding intervention period. Correlations were assessed between changes in myostatin and follistatin levels and measures of body composition and cardiometabolic biomarkers. Results There were no differences (p > 0.05) in circulating myostatin or follistatin levels between the beef intake groups. However, with beef groups combined myostatin decreased by 17.6% (p = 0.006) and the myostatin-to-follistatin ratio decreased by 16.5% (p 0.05) in circulating follistatin concentrations in response to the diet intervention. Conclusions The outcomes from this study suggest that a calorie-restricted DASH diet has the potential to reduce myostatin concentrations in older adults. Furthermore these outcomes support interrelationships between myostatin, body composition and cardiometabolic health in adults aged 65 years and older. Trial registration ClinicalTrials.gov; Identifier: NCT04127240 ; Registration Date: 15/10/ 2019.
... Firstly, FSTL3 is one of our most intriguing findings, in part, because of its emerging role in metabolic diseases [27]. FSTL3 is a circulating glycoprotein expressed in various tissues, including skeletal muscle [28]. It is known to form complexes with TGF-β family members, including activin A and myostatin, to inhibit their function [29,30]. ...
Skeletal muscle is highly plastic and dynamically regulated by the body’s physical demands. This study aimed to determine the plasticity of skeletal muscle DNA methylation in response to 8 weeks of supervised exercise training in volunteers with a range of insulin sensitivities. We studied 13 sedentary participants and performed euglycemic hyperinsulinemic clamps with basal vastus lateralis muscle biopsies and peak aerobic activity (VO2 peak) tests before and after training. We extracted DNA from the muscle biopsies and performed global methylation using Illumina’s Methylation EPIC 850K BeadChip. Training significantly increased peak aerobic capacity and insulin-stimulated glucose disposal. Fasting serum insulin and insulin levels during the steady state of the clamp were significantly lower post-training. Insulin clearance rates during the clamp increased following the training. We identified 13 increased and 90 decreased differentially methylated cytosines (DMCs) in response to 8 weeks of training. Of the 13 increased DMCs, 2 were within the following genes, FSTL3, and RP11-624M8.1. Of the 90 decreased DMCs, 9 were within the genes CNGA1, FCGR2A, KIF21A, MEIS1, NT5DC1, OR4D1, PRPF4B, SLC26A7, and ZNF280C. Moreover, pathway analysis showed an enrichment in metabolic and actin-cytoskeleton pathways for the decreased DMCs, and for the increased DMCs, an enrichment in signal-dependent regulation of myogenesis, NOTCH2 activation and transmission, and SMAD2/3: SMAD4 transcriptional activity pathways. Our findings showed that 8 weeks of exercise training alters skeletal muscle DNA methylation of specific genes and pathways in people with varying degrees of insulin sensitivity.
