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Impact of exogenous testosterone and AR (Flutamide/F)/IGF-IR (picropodophyllin/PPP) inhibitor co-incubations on MyoD, myogenin, AR and IGF-IR mRNA in CON and PD myoblasts after 72 h and 7 days. a Picropodophyllin alone significantly increased MyoD levels after 72 h (*P < 0.05). At 7 days, the presence of flutamide reduced MyoD expression levels in CON myoblasts (**P < 0.01). b In PD myoblasts, testosterone had no impact on MyoD levels at either time point. The presence of flutamide significantly reduced expression levels after 72 h (*P < 0.01) and 7 days (**P < 0.01). c Testosterone treatment significantly increased myogenin expression levels in CON myoblasts after 72 h (*P < 0.001). The presence of flutamide significantly reduced testosterone induced increases in myogenin (*P < 0.001). The presence of PPP did not significantly reduce increases in myogenin under a testosterone stimulus after 72 h culture. d In PD myoblasts, testosterone administration increased myogenin levels (P < 0.05) compared to un-treated cells. This observation was abrogated by the presence of flutamide and Picropodophyllin (*P < 0.05). At 7 days, there were no increases in myogenin expression with testosterone, however the presence of flutamide resulted in reduced levels (**P < 0.01). There was a significant difference between myogenin mRNA expression after 72 h and 7 days in untreated PD cells (***P < 0.01). e Testosterone co-incubated with flutamide significantly increased AR mRNA expression levels after 72 h in CON myoblasts (*P < 0.001). This effect was significantly reduced after 7 days (**P < 0.002). f In PD myoblasts, there significant reductions in AR expression with testosterone alone and in the presence of flutamide after 72 h (*P < 0.001). At 7 days, the addition of flutamide alone resulted in AR expression remaining decreased (**P < 0.001). g In CON myoblasts, flutamide significantly reduced IGF-IR expression (*P < 0.05) and Picropodophyllin significantly increased IGF-IR at the same time point (**P < 0.001). There were no observed alterations at 7 days exposure. h Flutamide significantly reduced IGF-IR expression after 72 h in PD myoblasts compared to un-treated cells (*P < 0.003). The presence of flutamide, after 7 days treatment, resulted in significant reductions in IGF-IR expression compared to basal conditions (**P < 0.01). Values presented as Mean ± SD
Source publication
We have previously highlighted the ability of testosterone (T) to improve differentiation and myotube hypertrophy in fusion impaired myoblasts that display reduced myotube hypertrophy via multiple population doublings (PD) versus their parental controls (CON); an observation which is abrogated via PI3K/Akt inhibition (Deane et al. 2013). However, w...
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Citations
... Moreover, testosterone stimulates the entrance of satellite cells into the cell cycle and their proliferation by suppressing myostatin expression [157,158]. Testosterone also improves the fusion of myoblasts and increases the utilization of amino acids from muscle breakdown [159][160][161]. Furthermore, testosterone also co-regulates mitochondrial biogenesis, dynamics, and autophagy with estradiol to maintain mitochondrial function in skeletal muscle [162]. ...
Sarcopenia is a skeletal muscle disorder characterized by progressive and generalized decline in muscle mass and function. Although it is mostly known as an age-related disorder, it can also occur secondary to systemic diseases such as malignancy or organ failure. It has demonstrated a significant relationship with adverse outcomes, e.g., falls, disabilities, and even mortality. Several breakthroughs have been made to find a pharmaceutical therapy for sarcopenia over the years, and some have come up with promising findings. Yet still no drug has been approved for its treatment. The key factor that makes finding an effective pharmacotherapy so challenging is the general paradigm of standalone/single diseases, traditionally adopted in medicine. Today, it is well known that sarcopenia is a complex disorder caused by multiple factors, e.g., imbalance in protein turnover, satellite cell and mitochondrial dysfunction, hormonal changes, low-grade inflammation, senescence, anorexia of aging, and behavioral factors such as low physical activity. Therefore, pharmaceuticals, either alone or combined, that exhibit multiple actions on these factors simultaneously will likely be the drug of choice to manage sarcopenia. Among various drug options explored throughout the years, testosterone still has the most cumulated evidence regarding its effects on muscle health and its safety. A mas receptor agonist, BIO101, stands out as a recent promising pharmaceutical. In addition to the conventional strategies (i.e., nutritional support and physical exercise), therapeutics with multiple targets of action or combination of multiple therapeutics with different targets/modes of action appear to promise greater benefit for the prevention and treatment of sarcopenia
... Additionally, simply measuring the change in the circulating concentration of a hormone may ultimately be too crude of a measure to explore these relationships in vivo given the likely influence of bioactivity via the dynamics of receptor concentration, interaction, and downstream signal transduction on these processes. One example is the activity and expression of the AR in skeletal muscle as the intracellular target of free testosterone (881). Acute high-volume resistance exercise increases AR phosphorylation (720,882) and AR DNA binding (230), and AR abundance is increased in response to resistance exercise training (870,(883)(884)(885). Notably, the increased abundance of AR is positively correlated with muscle hypertrophy (870,883), and high responders to resistance exercise training have higher AR abundance before and after training compared to low responders (884). ...
Repeated, episodic bouts of skeletal muscle contraction undertaken frequently as structured exercise training is a potent stimulus for physiological adaptation in many organs. Specifically in skeletal muscle, remarkable plasticity is demonstrated by the remodeling of muscle structure and function in terms of muscular size, force, endurance, and contractile velocity as a result of the functional demands induced by various types of exercise training. This plasticity, and the mechanistic basis for adaptations to skeletal muscle in response to exercise training, is underpinned by activation and/or repression of molecular pathways and processes induced in response to each individual acute exercise session. These pathways include the transduction of signals arising from neuronal, mechanical, metabolic, and hormonal stimuli through complex signal transduction networks, which are linked to a myriad of effector proteins involved in the regulation of pre- and post-transcriptional processes, and protein translation and degradation processes. This review therefore describes acute exercise-induced signal transduction and the molecular responses to acute exercise in skeletal muscle including emerging concepts such as epigenetic pre- and post-transcriptional regulation, and the regulation of protein translation and degradation. A critical appraisal of methodological approaches and the current state of knowledge informs a series of recommendations offered as future directions in the field.
... The above explanation demonstrates the process that occurs during muscle hyperplasia and hypertrophy. A similar concept has been affirmed by the work of Hughes et al. [60]. High testosterone accompanied by adequate nutrition can affect muscle mass and strength [58]. ...
Background and aim:
Pelung cockerels (Gallus gallus gallus [Linnaeus, 1758]) are different from other native cockerels in that they have a long and unique voice, in addition to their tall, large, and sturdy body with a relatively heavy body weight (BW). The sound quality of pelung cockerels is affected by the structure of the syrinx and their large and strong chest muscles. The performance of the chest muscles, and subsequently its voice, is influenced by the hormone testosterone. The shell of blood clams (Anadara granosa Linnaeus, 1758), a saltwater bivalve is known to contain a natural aromatase blocker (NAB) capable of blocking the aromatase enzyme from converting testosterone to estradiol. This generates consistently high levels of testosterone. This study aimed to determine the effect of blood clam shell powder (BCSP) as an NAB on the growth, pectoralis muscle performance, and testes of pelung cockerels.
Materials and methods:
The study design was a completely randomized design, with 16 pelung cockerels aged 40-56 weeks divided into four treatment groups: T0 (control); T1 (BCSP [A. granosa] 0.9 mg/kg BW); T2 (zinc sulfate [ZnSO4] 0.9 mg/kg BW); and T3 (testosterone 3 mg/day). The animals were acclimatized for 7 days and then given dietary treatments for 56 days. The measurement of the comb, wattle, and chest circumference (CC) of pelung cockerels was performed on days 0, 14, 28, 42, and 56. At the end of the treatment, the pelung cockerels were sacrificed and the data of the pectoralis muscle weight (PMW), testis weight (TW), and area of the pectoralis muscle (APM) were measured. Samples of pectoralis muscle and testes were taken and fixed in 10% neutral buffer formalin for histology. The proliferating cell nuclear antigen (PCNA) was identified by immunohistochemical staining. To measure fascicle area (FA), myofiber area (MA), and enumerate, the fascicle myofibers (NM) histology preparations were stained with hematoxylin and eosin (H and E). Testicular preparations were stained with H and E to measure the diameter of the seminiferous tubules (DST) using ImageJ software.
Results:
The growth performance on day 56 showed significantly (p < 0.05) higher differences of CC in T1 compared to T2 and T0, in T1 and T3 compared to T0, and in T3 and T2 compared to T0. Pectoralis muscle results, that is, FA, NM, MA, and PCNA-positive cells, showed that cockerels on treatment T3 had significantly higher results than other treatments, T1 was significantly different from T2 and T0, and T2 was significantly different from T0. In addition, the TW and DST measurement of cockerels on treatment T3 were significantly reduced (p < 0.05) than the other treatment groups.
Conclusion:
The oral administration of BCSP in the role of a NAB at a dose of 0.9 mg/kg BW for 56 days improved the growth performance and pectoralis muscle, especially the CC, FA, NM, MA, and PCNA-positive cells parameters, but did not affect the PMW, APM, and testis of pelung cockerels. The administration of testosterone at 3 mg/day for 56 days contributed to the decrease in TW and DST, as well as atrophy of the seminiferous tubules of pelung cockerels.
... Supplementation with testosterone promotes satellite cell entry into the cell cycle, thereby increasing the number of satellite cells (Hikim et al., 2002). Moreover, testosterone increases the response of fusionimpaired myoblasts, enhances AR levels, and increases the abundance of AKT expression (Hughes et al., 2016;Pal et al., 2019). In addition, testosterone improves the efficiency of amino acid utilization after proteolysis and promotes muscle synthesis (Ferrando et al., 1998). ...
Sarcopenia, a disorder characterized by age-related muscle loss and reduced muscle strength, is associated with decreased individual independence and quality of life, as well as a high risk of death. Skeletal muscle houses a normally mitotically quiescent population of adult stem cells called muscle satellite cells (MuSCs) that are responsible for muscle maintenance, growth, repair, and regeneration throughout the life cycle. Patients with sarcopenia are often exhibit dysregulation of MuSCs homeostasis. In this review, we focus on the etiology, assessment, and treatment of sarcopenia. We also discuss phenotypic and regulatory mechanisms of MuSC quiescence, activation, and aging states, as well as the controversy between MuSC depletion and sarcopenia. Finally, we give a multi-dimensional treatment strategy for sarcopenia based on improving MuSC function.
... Intra-group aggressivity could be crucial for high-dose irradiation models and (to some extent) concurrent immunosuppression. Although sex hormones affect IGF-1 signaling, testosterone seems to potentiate IGF-1 biological roles (Li and Li, 2014;Hughes et al., 2016), implying even higher effectivity in males. The second is associated with recommended doses of Increlex for humans, ranging from 0.04 to 0.12 mg/kg (Bang et al., 2022). ...
Purpose: Insulin-like growth factor-1 (IGF-1) stimulates epithelial regeneration but may also induce life-threatening hypoglycemia. In our study, we first assessed its safety. Subsequently, we examined the effect of IGF-1 administered in different dose regimens on gastrointestinal damage induced by high doses of gamma radiation.
Material and methods: First, fasting C57BL/6 mice were injected subcutaneously with IGF-1 at a single dose of 0, 0.2, 1, and 2 mg/kg to determine the maximum tolerated dose (MTD). The glycemic effect of MTD (1 mg/kg) was additionally tested in non-fasting animals. Subsequently, a survival experiment was performed. Animals were irradiated (⁶⁰Co; 14, 14.5, or 15 Gy; shielded head), and IGF-1 was administered subcutaneously at 1 mg/kg 1, 24, and 48 h after irradiation. Simultaneously, mice were irradiated (⁶⁰Co; 12, 14, or 15 Gy; shielded head), and IGF-1 was administered subcutaneously under the same regimen. Jejunum and lung damage were assessed 84 h after irradiation. Finally, we evaluated the effect of six different IGF-1 dosage regimens administered subcutaneously on gastrointestinal damage and peripheral blood changes in mice 6 days after irradiation (⁶⁰Co; 12 and 14 Gy; shielded head). The regimens differed in the number of doses (one to five doses) and the onset of administration (starting at 1 [five regimens] or 24 h [one regimen] after irradiation).
Results: MTD was established at 1 mg/kg. MTD mitigated lethality induced by 14 Gy and reduced jejunum and lung damage caused by 12 and 14 Gy. However, different dosing regimens showed different efficacy, with three and four doses (administered 1, 24, and 48 h and 1, 24, 48, and 72 h after irradiation, respectively) being the most effective. The three-dose regimens supported intestinal regeneration even if the administration started at 24 h after irradiation, but its potency decreased.
Conclusion: IGF-1 seems promising in the mitigation of high-dose irradiation damage. However, the selected dosage regimen affects its efficacy.
... Myogenin and focal adhesion kinase (FAK) are key players of skeletal myogenesis and are regulated by testosterone [39][40][41][42][43]. It is therefore important to address the effects of the peptides and testosterone on these two proteins. ...
... Myogenin is a muscle-specific member of the myo-D transcription factors that coordinates skeletal muscle development, myogenesis, and muscle repair [39]. Testosterone, whose administration increases skeletal muscle mass and strength [40,41], is a positive regulator of myogenin expression [54]. An essential phase of skeletal myogenesis is the fusion of mononucleated myoblasts to form multinucleated myotubes. ...
ZIP9 is a recently identified membrane-bound androgen receptor of physiological significance that may mediate certain physiological responses to androgens. Using in silico methods, six tetrapeptides with the best docking properties at the testosterone binding site of ZIP9 were synthesized and further investigated. All tetrapeptides displaced T-BSA-FITC, a membrane-impermeable testosterone analog, from the surface of mouse myogenic L6 cells that express ZIP9 but not the classical androgen receptor (AR). Silencing the expression of ZIP9 with siRNA prevented this labeling. All tetrapeptides were found to be pro-androgenic; in L6 cells they stimulated the expression of myogenin, triggered activation of focal adhesion kinase, and prompted the fusion of L6 myocytes to syncytial myotubes. In human osteoblastic SAOS-2 cells that express AR and ZIP9, they reduced the expression of alkaline phosphatase and stimulated mineralization. These latter effects were prevented by silencing ZIP9 expression, indicating that the osteoblast/osteocyte conversion is exclusively mediated through ZIP9. Our results demonstrate that the synthetic tetrapeptides, by acting as ZIP9-specific androgens, have the potential to replace testosterone or testosterone analogs in the treatment of bone- or muscle-related disorders by circumventing the undesirable effects mediated through the classical AR.
... Myoblast differentiation is orchestrated by complex programmes of cell signalling [19] and altered gene expression [17] that result in dynamic changes to the cell proteome during differentiation [20,21]. Accordingly, the reductions in differentiation and fusion capacity of replicatively aged cells are accompanied by impaired cell signalling and gene expression [22,23]. Insulin-like growth factors I/II (IGF-I and II) are critical for cell proliferation, differentiation and growth [24] and are key regulators of muscle hypertrophy. ...
Age-related impairments in myoblast differentiation may contribute to reductions in muscle function in older adults, however, the underlying proteostasis processes are not well understood. Young (P6-10) and replicatively aged (P48-50) C2C12 myoblast cultures were investigated during early (0h-24h) and late (72h-96h) stages of differentiation using deuterium oxide (D2O) labelling and mass spectrometry. The absolute dynamic profiling technique for proteomics (Proteo-ADPT) was applied to quantify the absolute rates of abundance change, synthesis and degradation of individual proteins. Proteo-ADPT encompassed 116 proteins and 74 proteins exhibited significantly (P<0.05, FDR <5 %) different changes in abundance between young and aged cells at early and later periods of differentiation. Young cells exhibited a steady pattern of growth, protein accretion and fusion, whereas aged cells failed to gain protein mass or undergo fusion during later differentiation. Maturation of the proteome was retarded in aged myoblasts at the onset of differentiation, but their proteome appeared to "catch up" with the young cells during the early phase of the differentiation period. However, this "catch up" process in aged cells was not accomplished by higher levels of protein synthesis. Instead, a lower level of protein degradation in aged cells was responsible for the elevated gains in protein abundance. Our novel data point to a loss of proteome quality as a precursor to the lack of fusion of aged myoblasts and highlights dysregulation of protein degradation, particularly of ribosomal and chaperone proteins, as a key mechanism that may contribute to age-related declines in the capacity of myoblasts to undergo differentiation.
... Not only that, recent studies showed the importance of PI3K/Akt, p38 and ERK1/2 MAPKs in the anabolic action of AR, which was partly fulfilled through the crosstalk with AR [35][36][37].Testosterone promotes muscle hypertrophy via activating PI3K/Akt [35], ERK1/2 [36] and p38 MAPK [37], and administration of specific inhibitors of PI3K (LY294002) and p38 (SB203580) block the testosterone's effects. In fact, in addition to AR-induced myotube hypertrophy, testosterone-induced differentiation (increases of myotube number and diameter) of fusion impaired C2C12 myoblasts is also associated with the activation of PI3K/Akt [38] and androgen/AR-participated skeletal muscle glucose metabolism is related to the activations of Akt and ERK1/2 signal pathways [39]. ...
Background
Androgen receptor (AR) exerts important roles in exercise-induced alterations of muscle mass, in which the proliferation and differentiation of satellite cells or myoblasts are crucial. Our previous study in C2C12 myoblasts demonstrated that 15% (mimic appropriate exercise) and 20% (mimic excessive exercise) stretches promoted and inhibited the proliferation respectively; and AR played a crucial role in 15% stretch-induced pro-proliferation through IGF-1-modulated PI3K/Akt, p38 and ERK1/2 pathways, but AR’s role in stretches-modulated proliferation of general myoblasts, especially 20% stretch, remains unclear, and the mechanisms need to be further clarified.
Methods
Firstly, the discrepancy in proliferation and the above indicators between L6 (without AR) and C2C12 (with AR) myoblasts were compared under 15% or 20% stretch. Then the influences of transfection AR or exogenous IGF-1 treatment on proliferation and these indicators were detected in stretched L6 myoblasts.
Results
(1) Under un-stretched state, the proliferation of L6 was slower than C2C12 cells. Furthermore, AR knockdown in C2C12 myoblasts repressed, while AR overexpression in L6 myoblasts promoted the proliferation. (2) 15% stretch-induced increases in the proliferation and activities of p38 and ERK1/2 were lower in L6 than C2C12 cells; AR overexpression enhanced the proliferation of 15% stretched L6 cells accompanied with the increases of p38 and ERK1/2 activities. (3) 20% stretch-induced anti-proliferation and inhibition of p38 activity were severer in L6 than C2C12 myoblasts; AR overexpression reversed the anti-proliferation of 20% stretch and enhanced p38 activity in L6 myoblasts. (4) In stretched L6 myoblasts, AR overexpression increased IGF-1R level despite no detectable IGF-1; and recombinant IGF-1 increased the proliferation, the level of IGF-1R, and the activities of p38 and ERK1/2 in 15% stretched L6 myoblasts.
Conclusions
The study demonstrated AR's crucial roles in stretches-regulated proliferation of myoblasts, and increased AR fulfilled 15% stretch's pro-proliferation via activating IGF-1R- p38 and ERK1/2 pathways while decreased AR achieved 20% stretch's anti-proliferation via inhibiting IGF-1R- p38 pathway, which is useful to understand in depth the role and mechanisms of AR in appropriate exercise increasing while excessive exercise decreasing muscle mass.
... Not only that, recent studies showed the importance of PI3K/Akt, p38 and ERK1/2 MAPKs in the anabolic action of AR, which was partly ful lled through the crosstalk with AR [35][36][37]. Testosterone promotes muscle hypertrophy via activating PI3K/Akt [35], ERK1/2 [38] and p38 MAPK [39], and administration of speci c inhibitors of PI3K (LY294002) and p38 (SB203580) blocked the testosterone's effects. In fact, in addition to AR-induced myotube hypertrophy, testosterone-induced differentiation (increases of myotube number and diameter) of fusion impaired C2C12 myoblasts is also associated with the activation of PI3K/Akt [37] and androgen/AR-participated skeletal muscle glucose metabolism is related to the activations of Akt and ERK1/2 signal pathways [36]. ...
... Testosterone promotes muscle hypertrophy via activating PI3K/Akt [35], ERK1/2 [38] and p38 MAPK [39], and administration of speci c inhibitors of PI3K (LY294002) and p38 (SB203580) blocked the testosterone's effects. In fact, in addition to AR-induced myotube hypertrophy, testosterone-induced differentiation (increases of myotube number and diameter) of fusion impaired C2C12 myoblasts is also associated with the activation of PI3K/Akt [37] and androgen/AR-participated skeletal muscle glucose metabolism is related to the activations of Akt and ERK1/2 signal pathways [36]. ...
Background
Our previous study has indicated that in C2C12 myoblasts androgen receptor (AR) plays a crucial role in 15% stretch-induced proliferation through insulin-like growth factor (IGF-1)-modulated PI3K/Akt, p38 and ERK1/2 pathways. In this study we further explored AR's effects on 15% and 20% stretches-modulated myoblasts proliferation and involved pathways in L6 (no detectable AR) and C2C12 (abundant AR) myoblasts.Methods
The proliferation and the above indicators were compared between stretched L6 and C2C12 myoblasts by CCK8, ELISA and Western blot, then were detected again in stretched L6 myoblasts after transfection with AR overexpression plasmid utilizing LipoPlus TM 2000 reagent or treatment with different concentrations (200, 500, 1000 ng/ml) IGF-1 recombinant polypeptide.ResultsWe found that ①Under un-stretched states, the proliferation rate of L6 cells was slower than that of C2C12 cells, and the proliferation of C2C12 cells was repressed by AR knockdown using siRNA interference, while L6 myoblasts proliferation was promoted by overexpression AR. ②The proliferation rate as well as the activities of p38 and ERK1/2 increased by 15% stretch were much lower in L6 than that in C2C12 cells; AR overexpression enhanced the proliferation of 15% stretched L6 cells accompanied with increased activities of p38 and ERK1/2; ③20% stretch decreased the proliferation and activity of p38 in L6 more than that in C2C12 myoblasts; overexpression of AR totally reversed the anti-proliferation of 20% stretch and significantly enhanced p38 activity in L6 myoblasts;④In L6 myoblasts, overexpression AR increased IGF-1R expression despite no detectable IGF-1 was secreted; and recombinant IGF-1 increased not only the proliferation, but also the protein level of IGF-1R and activities of p38 and ERK1/2 in a dose-dependent manner in 15% stretched L6 myoblasts. ConclusionsAR fulfilled 15% stretch-induced pro-proliferation of myoblasts by activating IGF-1R-p38 and ERK1/2 pathways, while 20% stretch-induced anti-proliferation was mediated by inhibiting AR-IGF-1R-p38 pathway. This study is beneficial to understand in depth the role and mechanisms of AR on appropriate exercise increases while excessive exercise decreases muscle mass.
... 37 Taken together, our data suggested that senescent SkM tissues failed to regenerate, possibly as a result of protracted apoptosis, depletion of satellite cells, and failure to initiate proliferation and subsequent fusion to form de novo myofibers. It would be interesting to use this system to test chemical and biological compounds such as hormones, 38,39 antioxidants, or mechanical forces, alone or in combination, to examine whether they can improve or even reverse the regeneration capacity of human senescent myofibers. In summary, our findings indicate that similar to aged organisms, senescent 3D SkM constructs exhibited impaired ability to regenerate in response to injury and therefore, they may provide a model to study senescence, wound healing, and muscle wasting disorders, and also provide a platform for pharmacological testing in a 3D setting that better mimics the in vivo behavior of SkM tissue. ...
With age adult skeletal muscle (SkM) is known to decrease in muscle mass, strength and functional capacity, a state known as sarcopenia. Here we developed an in vitro three-dimensional (3D) bioengineered senescent skeletal muscle (SkM) tissue using primary human myoblasts. These tissues exhibited the characteristics of atrophied muscle, including expression of senescent genes, decreased number of satellite cells, reduced number and size of myofibers and compromised metabolism and calcium flux. As a result, senescent SkM tissues showed impaired ability to generate force in response to electrical stimulation as compared to young tissues. Furthermore, in contrast to young SkM tissues, senescent tissues failed to regenerate in response to injury, possibly as a result of persistent apoptosis and failure to initiate a proliferation program. Our findings suggest that 3D senescent SkM may provide a powerful model for studying aging and a platform for drug testing and discovery of therapeutic compounds to improve the function of sarcopenic muscle.
