Muscle Myostatin Research Articles

6979 Effect of Orchiectomy on Muscle Growth and Differentiation Factors in Male Mice With Kidney Disease

Abstract Disclosure: O. Marks: None. J. Bruno: None. D. Wu: None. A. Patwardhan: None. Y. Komaru: None. G. Ling: None. E. Kefalogianni: None. R. Aurora: None. S.S. Dhindsa: None. A. Herrlich: None. Background: Sarcopenia and frailty are major clinical concerns in participants with chronic kidney disease (CKD). In males, an additional factor contributes to the development of sarcopenia. Around half of the men with CKD have subnormal serum testosterone (T) concentrations. The mechanisms that underlie the effect of low T concentrations on muscle growth in CKD are not known. In this study, we performed orchiectomy in male mice with kidney disease and evaluated the expression and protein content of the following muscle growth and differentiation factors. Methods: Forty mice were divided into 4 groups: 1) renal injury, induced by ischemia-induced reperfusion (IRI, N=11) at 2 months of age; 2) orchidectomy (ORX), performed 4 weeks after IRI (IRI + ORX, N=9); 3) sham-IRI and ORX (sham-ORX, N=8); and 4) sham-sham surgery (N=12). The mice were sacrificed when they were ∼7 months old (mean age 206±13 days). Gastrocnemius and levator ani muscles were harvested to measure expression by RT-qPCR of muscle catabolism markers (Atrogin-1 and ubiquitin ligase MuRF1), muscle growth inhibitors, myostatin and myogenic regulatory factor (Mrf4), fibroblast growth factor-2 (FGF2, a stimulator of satellite stem cells) and its receptor FGFR2, androgen receptor (AR) and IGF-1. Results: The mean BUN (blood urea nitrogen) at the time of sacrifice was higher in the IRI/ORX (32±4 mg/dl) and IRI/Sham (26±5 mg/dl) groups as compared to sham-sham (21±5 mg/dl, p<0.05 for both). There was a significant reduction (p<0.05) in the expression of myostatin (by 41%), Mrf4 (29%), atrogin-1 (51%) and MuRF1 (32%) in gastrocnemius muscle from the ORX-IRI and ORX-sham groups, while there was no difference in FGF2 and FGFR2, as compared to sham-sham group. Data from levator ani muscle (the most androgen sensitive muscle in mammals) showed increases in AR (64%) and Atrogin-1 (66%); and decreases in IGF-1 (88%) and myostatin (86%) in ORX-IRI and ORX-sham groups. Consistent with the mRNA expression, we found a drastic decline in protein content of myostatin in gastrocnemius (85%) in ORX-IRI and ORX-sham groups as compared to sham-sham (p=0.04). Conclusions: These data show that ORX in mice with renal injury is associated with changes in muscle growth and differentiation factors. Myostatin was the most affected gene, with 41-86% decline in mRNA and protein. These data are informative for attempts to develop treatments for sarcopenia in patients with kidney disease. Limitations: Our experimental model differs in some respects from hypogonadal men with CKD. ORX results in complete elimination of T, and thus much lower T concentrations than in men with kidney disease. There is a recovery of kidney function after IRI. We sacrificed the mice 5 months after renal injury was inflicted. Hence, the effect of IRI on muscle growth genes may have been different immediately following IRI. Thus, the impact of ORX was more apparent than of IRI in our study. Presentation: 6/1/2024

6979 Effect of Orchiectomy on Muscle Growth and Differentiation Factors in Male Mice With Kidney Disease

Abstract Disclosure: O. Marks: None. J. Bruno: None. D. Wu: None. A. Patwardhan: None. Y. Komaru: None. G. Ling: None. E. Kefalogianni: None. R. Aurora: None. S.S. Dhindsa: None. A. Herrlich: None. Background: Sarcopenia and frailty are major clinical concerns in participants with chronic kidney disease (CKD). In males, an additional factor contributes to the development of sarcopenia. Around half of the men with CKD have subnormal serum testosterone (T) concentrations. The mechanisms that underlie the effect of low T concentrations on muscle growth in CKD are not known. In this study, we performed orchiectomy in male mice with kidney disease and evaluated the expression and protein content of the following muscle growth and differentiation factors. Methods: Forty mice were divided into 4 groups: 1) renal injury, induced by ischemia-induced reperfusion (IRI, N=11) at 2 months of age; 2) orchidectomy (ORX), performed 4 weeks after IRI (IRI + ORX, N=9); 3) sham-IRI and ORX (sham-ORX, N=8); and 4) sham-sham surgery (N=12). The mice were sacrificed when they were ∼7 months old (mean age 206±13 days). Gastrocnemius and levator ani muscles were harvested to measure expression by RT-qPCR of muscle catabolism markers (Atrogin-1 and ubiquitin ligase MuRF1), muscle growth inhibitors, myostatin and myogenic regulatory factor (Mrf4), fibroblast growth factor-2 (FGF2, a stimulator of satellite stem cells) and its receptor FGFR2, androgen receptor (AR) and IGF-1. Results: The mean BUN (blood urea nitrogen) at the time of sacrifice was higher in the IRI/ORX (32±4 mg/dl) and IRI/Sham (26±5 mg/dl) groups as compared to sham-sham (21±5 mg/dl, p<0.05 for both). There was a significant reduction (p<0.05) in the expression of myostatin (by 41%), Mrf4 (29%), atrogin-1 (51%) and MuRF1 (32%) in gastrocnemius muscle from the ORX-IRI and ORX-sham groups, while there was no difference in FGF2 and FGFR2, as compared to sham-sham group. Data from levator ani muscle (the most androgen sensitive muscle in mammals) showed increases in AR (64%) and Atrogin-1 (66%); and decreases in IGF-1 (88%) and myostatin (86%) in ORX-IRI and ORX-sham groups. Consistent with the mRNA expression, we found a drastic decline in protein content of myostatin in gastrocnemius (85%) in ORX-IRI and ORX-sham groups as compared to sham-sham (p=0.04). Conclusions: These data show that ORX in mice with renal injury is associated with changes in muscle growth and differentiation factors. Myostatin was the most affected gene, with 41-86% decline in mRNA and protein. These data are informative for attempts to develop treatments for sarcopenia in patients with kidney disease. Limitations: Our experimental model differs in some respects from hypogonadal men with CKD. ORX results in complete elimination of T, and thus much lower T concentrations than in men with kidney disease. There is a recovery of kidney function after IRI. We sacrificed the mice 5 months after renal injury was inflicted. Hence, the effect of IRI on muscle growth genes may have been different immediately following IRI. Thus, the impact of ORX was more apparent than of IRI in our study. Presentation: 6/1/2024

Taldefgrobep Alfa and the Phase 3 RESILIENT Trial in Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is a rare, genetic neurodegenerative disorder caused by insufficient production of survival motor neuron (SMN) protein. Diminished SMN protein levels lead to motor neuron loss, causing muscle atrophy and weakness that impairs daily functioning and reduces quality of life. SMN upregulators offer clinical improvements and increased survival in SMA patients, although significant unmet needs remain. Myostatin, a TGF-β superfamily signaling molecule that binds to the activin II receptor, negatively regulates muscle growth; myostatin inhibition is a promising therapeutic strategy for enhancing muscle. Combining myostatin inhibition with SMN upregulation, a comprehensive therapeutic strategy targeting the whole motor unit, offers promise in SMA. Taldefgrobep alfa is a novel, fully human recombinant protein that selectively binds to myostatin and competitively inhibits other ligands that signal through the activin II receptor. Given a robust scientific and clinical rationale and the favorable safety profile of taldefgrobep in patients with neuromuscular disease, the RESILIENT phase 3, randomized, placebo-controlled trial is investigating taldefgrobep as an adjunct to SMN upregulators in SMA (NCT05337553). This manuscript reviews the role of myostatin in muscle, explores the preclinical and clinical development of taldefgrobep and introduces the phase 3 RESILIENT trial of taldefgrobep in SMA.

Investigation of the relationship between plasma ghrelin levels and muscle atrophy in experimental diabetic rats

In this study, the relationship between plasma ghrelin levels and muscle atrophy was examined in an experimental diabetic rat model. 56 male Wistar albino rats, aged 8-10 weeks, were used in the study. The rats were divided into 8 groupsD1: one-week diabetes, C1: one-week control, D2: three-week diabetes, C2: three-week control, D3: six-week diabetes, C3: six-week control, D4: eight-week diabetes, C4: eight-week control. To induce diabetes, rats were injected with a single intraperitoneal dose of 45 mg/kg streptozotocin. At the end of the experiments, body weights and fasting blood sugar levels were measured. mTOR and myostatin levels of gastrocnemius muscle and plasma ghrelin levels were measured by ELISA method. Gastrocnemius muscle weight, cross-sectional area and histopathological images were examined. It was observed that the gastrocnemius weights of the D2, D3, D4 groups decreased significantly compared to their controls (p≤0.01). Muscle cross-sectional area decreased significantly in groups D3 and D4 compared to controls (p≤0.01). Muscle mTOR levels were found to be significantly lower in all diabetic groups compared to controls (p≤0.01). Although muscle myostatin levels were higher in the diabetic groups, this increase was only significant in the D4 group. Plasma ghrelin levels were significantly lower in all diabetic groups compared to controls (p≤0.01). A positive correlation was determined between plasma ghrelin levels and the final weights, muscle cross-sectional area, gastrocnemius weights and mTOR levels of the rats. Time-dependent muscle atrophy developed in diabetic rats and there was a relationship between muscle atrophy and plasma ghrelin level. We suggest that ghrelin plays a role in diabetes-induced muscle atrophy as well as cachexia and sarcopenia.

Mechanism and physical activities in bone-skeletal muscle crosstalk.

Bone and skeletal muscle work in coordination to maintain the function of the musculoskeletal system, in which skeletal muscle contraction drives the movement of the bone lever system while bone provides insert sites for skeletal muscle through the bone-muscle junction. Existing evidence suggests that factors secreted by skeletal muscle and bone mediate the interaction between the two tissues. Herein, we focused on the relationship between skeletal muscle and bone and the underlying mechanism of the interaction. Exercise can promote bone strength and secrete osteocalcin and insulin-like growth factor I into the blood, thus improving muscle quality. In addition, exercise can also promote myostatin, interleukin-6, Irisin, and apelin in muscles to enter the blood so that they can act on bones to maintain the balance between bone absorption and bone formation. There is a special regulatory axis interleukin-6/osteocalcin between myokines and osteokines, which is mainly influenced by exercise. Therefore, we pay attention to the important factors in the bone-muscle intersection that are affected by exercise, which were found or their functions were expanded, which strengthened the connection between organs of the whole body, highlighting the importance of exercise and contributing to the diagnosis, prevention, and treatment of osteoporosis and sarcopenia in the clinic.

Mouse skeletal muscle adaptations to different durations of treadmill exercise after the cessation of FOLFOX chemotherapy.

FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) chemotherapy is a treatment for colorectal cancer that can induce persistent fatigue and metabolic dysfunction. Regular exercise after chemotherapy cessation is widely recommended for cancer patients and has been shown to improve fatigue resistance in mice. However, gaps remain in understanding whether the early systemic and skeletal muscle adaptations to regular exercise are altered by prior FOLFOX chemotherapy treatment. Furthermore, the effects of exercise duration on early metabolic and skeletal muscle transcriptional adaptations are not fully established. Purpose: Investigate the effects of prior FOLFOX chemotherapy treatment on the early adaptations to repeated short- or long-duration treadmill exercise, including the fasting regulation of circulating metabolic regulators, skeletal muscle COXIV activity and myokine/exerkine gene expression in male mice. Methods: Male C57BL6/J mice completed 4 cycles of FOLFOX or PBS and were allowed to recover for 4-weeks. Subsets of mice performed 14 sessions (6d/wk, 18m/min, 5% grade) of short- (10min/d) or long-duration (55min/d) treadmill exercise. Blood plasma and muscle tissues were collected 48-72h after the last exercise bout for biochemical analyses. Results: Long-duration exercise increased fasting plasma osteocalcin, LIF, and IL-6 in healthy PBS mice, and these changes were ablated by prior FOLFOX treatment. Slow-oxidative soleus muscle COXIV activity increased in response to long-duration exercise in PBS mice, which was blocked by prior FOLFOX treatment. Fast-glycolytic plantaris muscle COXIV activity increased with short-duration exercise independent of FOLFOX administration. There was a main effect for long-duration exercise to increase fasting muscle IL-6 and COXIV mRNA expression independent of FOLFOX. FOLFOX administration reduced muscle IL-6, LIF, and BDNF mRNA expression irrespective of long-duration exercise. Interestingly, short-duration exercise suppressed the FOLXOX induction of muscle myostatin mRNA expression. Conclusion: FOLFOX attenuated early exercise adaptations related to fasting circulating osteocalcin, LIF, and IL-6. However, prior FOLFOX treatment did not alter the exercise adaptations of plantaris muscle COXIV activity and plasma adiponectin. An improved understanding of mechanisms underlying exercise adaptations after chemotherapy will provide the basis for successfully treating fatigue and metabolic dysfunction in cancer survivors.

Skeletal muscle myostatin mRNA expression is upregulated in aged human adults with excess adiposity but is not associated with insulin resistance and ageing.

Myostatin negatively regulates skeletal muscle growth and appears upregulated in human obesity and associated with insulin resistance. However, observations are confounded by ageing, and the mechanisms responsible are unknown. The aim of thisstudy wasto delineate between the effects of excess adiposity, insulin resistance and ageing on myostatin mRNA expression in human skeletal muscle and to investigate causative factors using in vitro models. An in vivo cross-sectional analysis of human skeletal muscle was undertaken to isolate effects of excess adiposity and ageing per se on myostatin expression. In vitro studies employed human primary myotubes to investigate the potential involvement of cross-talk between subcutaneous adipose tissue (SAT) and skeletal muscle, and lipid-induced insulin resistance. Skeletal muscle myostatin mRNA expression was greater in aged adults with excess adiposity than age-matched adults with normal adiposity (2.0-fold higher; P < 0.05) and occurred concurrently with altered expression of genes involved in the maintenance of muscle mass but did not differ between younger and aged adults with normal adiposity. Neither chronic exposure to obese SAT secretome nor acute elevation of fatty acid availability (which induced insulin resistance) replicated the obesity-mediated upregulation of myostatin mRNA expression in vitro. In conclusion,skeletal muscle myostatin mRNA expression is uniquely upregulated in aged adults with excess adiposity and insulin resistance but not by ageing alone. This does not appear to be mediated by the SAT secretome or by lipid-induced insulin resistance. Thus, factors intrinsic to skeletal muscle may be responsible for the obesity-mediated upregulation of myostatin, and future work to establish causality is required.

Telmisartan versus metformin in downregulating myostatin gene expression and enhancing insulin sensitivity in the skeletal muscles of type 2 diabetic rat model.

Objective: Telmisartan is an angiotensin receptor blocker (ARB) that specifically blocks angiotensin II type-1 receptors (AT1R). Telmisartan has been proven to have antidiabetic effects via a variety of mechanisms, and it can be utilized in some diabetic patients due to its dual benefit for hypertensive patients with type 2 DM (T2DM) and when the other oral antidiabetic medications are intolerable or contraindicated. However, its precise underlying hypoglycemic mechanism is still obscure. Aim of work: We sought to establish a link between telmisartan administration and myostatin expression in skeletal muscles of T2DM rat model as a potential hypoglycemic mechanism of telmisartan. Materials and Methods: 32 male albino rats were included in the study; 8 rats served as controls (group I). T2DM was inducted in the other 24 rats, which were then randomly subdivided into 3 groups (8 in each): (group II) the Diabetic group and (groups III and IV) which were treated with either telmisartan (8mg/kg/day) or metformin (250mg/kg/day) respectively via oral gavage for a 4-week period. Results: Telmisartan administration resulted in a significant improvement in OGTT, HOMA-IR, glucose uptake, and muscle mass/body ratios in Telmisartan group as compared to Diabetic group (p < 0.05). Additionally, telmisartan induced a significant boost in adiponectin and IL-10 serum levels with a substantial drop in TNF-α and IL-6 levels in Telmisartan group compared to diabetic rats (p < 0.05). Moreover, telmisartan significantly boosted SOD and GSH, and decreased MDA levels in the skeletal muscles of telmisartan group. Furthermore, a significant downregulation of myostatin and upregulation of insulin receptor, IRS-1, and IRS-3 genes in the skeletal muscles of Telmisartan group were also detected. Histologically, telmisartan attenuated the morphological damage in the skeletal muscle fibers compared to diabetic rats, as evidenced by a considerable decrease in the collagen deposition area percentage and a reduction in NF-kB expression in the muscle tissues of group III. Conclusion: Telmisartan administration dramatically reduced myostatin and NF-kB expressions in skeletal muscles, which improved insulin resistance and glucose uptake in these muscles, highlighting a novel antidiabetic mechanism of telmisartan in treating T2DM.

Impacts of supplemental Ginkgo biloba oil on broilers’ growth, blood indices, intestinal and hepatic morphology and expression of growth-related genes

The current work examined the impact of Ginkgo biloba oil (GBO) on growth performance, some biochemical parameters, intestinal and hepatic morphology, economic efficiency and expression of some growth-related genes in broiler chickens. A total of 135 chicks (Cobb 500) were allotted into three groups with 3 replications (15 birds/replicate). The experimental groups included: G1 (control), G2 and G3 were supplemented with GBO in the drinking water (0.25 and 0.5 cm/L), respectively. The GBO was added to the drinking water only for 3 successive weeks. Compared to the other groups, supplementation with 0.25 cm/L GBO significantly (P ≤ 0.05) increased final body weight, overall weight gain, feed intake and water consumption. When 0.25 cm GBO/L was added, that group significantly differed in intestinal villus length (P ≤ 0.05). Birds received 0.25 cm GBO/L had significantly greater blood total albumin and total protein concentrations (P ≤ 0.05), while birds given 0.5 cm GBO/L had higher serum cholesterol and LDL concentrations (P ≤ 0.05). The cost parameters were significantly higher (P ≤ 0.05) in the 0.25 cm GBO/L supplemented group, which exhibited higher total return and net profit. The addition of 0.25 cm GBO/L resulted in higher expression of antioxidant enzymes and insulin-like growth factor while inhibiting the expression of Myostatin in muscles (P < 0.05) compared to the control and those received 0.5 cm GBO/L. In conclusion, broiler chickens that received 0.25 cm GBO/L for 3 consecutive days per week had better performance, intestinal morphology, profitability, and antioxidant status than the control birds.

Resistance Exercise-Induced Increases in Muscle Myostatin mRNA and Protein Expression Are Subsequently Decreased in Circulation in the Presence of Increased Levels of the Extracellular Matrix Stabilizing Protein Decorin.

Resistance exercise (RE) activates cell signaling pathways associated with myostatin. Decorin is located in the extracellular matrix (ECM) and can block the inhibitory effect of myostatin. This study sought to determine the impact of low-load (LL) and high-load (HL) RE on myostatin mRNA and protein expression along with changes in muscle decorin and circulating follistatin. Ten resistance-trained men performed a LL (50% 1RM) and HL (80% 1RM) RE session using the angled leg press and leg extension with load and volume equated. Venous blood samples and muscle biopsies were obtained prior to and at 3h and 24h following each RE session. Muscle myostatin mRNA expression was increased at 24h post-exercise (p = 0.032) in LL and at 3h (p = 0.044) and 24h (p = 0.003) post-exercise in HL. Muscle decorin was increased at 24h post-exercise (p < 0.001) in LL and HL; however, muscle myostatin was increased at 24h post-exercise (p < 0.001) only in HL. For muscle Smad 2/3, no significant differences were observed (p > 0.05). Serum follistatin was increased and myostatin decreased at 24h post-exercise (p < 0.001) in LL and HL. Muscle myostatin gene and protein expression increased in response to HL RE. However, serum myostatin was decreased in the presence of increases in decorin in muscle and follistatin in circulation. Therefore, our data suggest a possible mechanism may exist where decorin within the ECM is able to bind to, and decrease, myostatin that might otherwise enter the circulation for activin IIB (ACTIIB) receptor binding and subsequent canonical signaling through Smad 2/3.

Exploring mitigating role of zinc nanoparticles on arsenic, ammonia and temperature stress using molecular signature in fish

BackgroundThe pollution and climate change in aquatic ecosystems are major problems threatening the aquatic organisms for existence in the recent timeline, which promotes the extinction of the fish species. However, the present study dealt with zinc nanoparticles (Zn-NPs) in mitigating arsenic, ammonia and high temperature stresses in Pangasianodon hypophthalmus. Materials and methodsTo studying different gene expressions, an experiment was conducted to mitigate the multiple stressors using dietary Zn-NPs at 0, 2, 4, and 6 mg kg-1 diets. In the present investigation, the gene expressions studies were performed for growth hormone regulator 1 (GHR1), growth hormone regulator β (GHRβ), growth hormone (GR) in liver and gill tissue as well as myostatin (MYST) and somatostatin (SMT) in the muscle tissue. The anti-oxidative genes CAT, SOD and GPx in liver and gill tissues were also analysed. Expression studies for stress responsive heat shock protein gene (HSP70), DNA damage inducible protein, inducible nitric oxide synthase (iNOS), immune related genes such as interleukin (IL), tumour necrosis factor (TNFα), toll like receptor (TLR) and immunoglobulin were performed. At the end of the experiment the fish were infected with Aeromonas hydrophila to evaluate the immunomodulatory role of Zn-NPs. ResultsIn the present investigation, the growth hormone regulator 1 (GHR1), growth hormone regulator β (GHRβ), growth hormone (GR) in liver and gill as well as myostatin (MYST) and somatostatin (SMT) in muscle were noticeably altered, whereas, Zn-NPs at 4 mg kg-1 diet improved gene expressions. The anti-oxidant gene viz. CAT, SOD and GPx in liver and gill tissues were upregulated by stressors such as As, NH3, NH3+T. As+T and As+NH3+T. Therefore, anti-oxidant genes were noticeably improved with dietary Zn-NPs diet. The stress protein gene (HSP70), DNA damage inducible protein, inducible nitric oxide synthase (iNOS) was significantly upregulated, whereas, Zn-NPs diet was applied to the corrected gene regulation. Similarly, immune related genes such as interleukin (IL), tumour necrosis factor (TNFα), toll like receptor (TLR) and immunoglobulin were highly affected by stressors. Dietary Zn-NPs at 4 mg kg-1 diet was improved all the immune related gene expression and mitigate arsenic, ammonia and high temperature stress in fish. ConclusionThe present investigation revealed that Zn-NPs at 4.0 mg kg-1 diet has enormous potential to modulates arsenic, ammonia and high temperature stress, and protect against pathogenic infections in fish.

Effect of thermal manipulation during embryogenesis on gene expression of myogenic regulatory factors pre and post hatch in broilers

A total of 1,440 fertile eggs were divided randomly and equally into 5 treatment groups; control (no TM) and 4 treatment groups: TM1, TM2, TM3, and TM4 that were thermally subjected to 39°C for 18 h with 65% relative humidity daily, during embryonic days ED 7–11, ED 11–15, ED 15–18 and ED 7–18, respectively. Out of TM conditions that were investigated, TM1 resulted in a significant improvement in expression of myogenic factor-5 (Myf5), myoblast determination protein (MyoD) and myogenin (MyoG) in pre and post hatch broiler muscle when compared to the control. This study aimed to determine the optimum time for thermal manipulation during embryogenesis that may result in improvement in expression of myogenic regulatory factors (MRFs): Myf5, MyoD, MyoG and myostatin (MSTN) in broiler muscle. Thus, the results of this research may provide a means of improvement of myogenesis of pectoral and thigh muscles of broilers proceeding from early embryogenesis (ED7) through post-hatch day.

Whole Body Vibration Improves Brain and Musculoskeletal Health by Modulating the Expression of Tissue-Specific Markers: FNDC5 as a Key Regulator of Vibration Adaptations.

Whole body vibration (WBV) is well known to exert beneficial effects on multiple tissues, improving synaptic transmission, muscle mass, bone quality, and reducing anxiety and depressive behavior. However, the underlying molecular mechanisms are not yet fully understood, and organs and tissues may respond differently to the vibratory stimulus depending on multiple factors. Therefore, we investigated the WBV effects on the brain and musculoskeletal tissue of 4-month-old young mice, evaluating synaptic plasticity by electrophysiological recordings and tissue organization by histology and histomorphometric analysis. Specifically, WBV protocols were characterized by the same vibration frequency (45 Hz), but different in vibration exposure time (five series of 3 min for the B protocol and three series of 2 min and 30 s for the C protocol) and recovery time between two vibration sessions (1 min for the B protocol and 2 min and 30 s for the C protocol). In addition, immunohistochemistry was conducted to evaluate the expression of fibronectin type III domain-containing protein 5 (FNDC5), as well as that of tissue-specific markers, such as brain-derived neurotrophic factor (BDNF) in brain, myostatin in muscle and collagen I (COL-1) in bone. Our results suggest that the WBV effects depend closely on the type of protocol used and support the hypothesis that different organs or tissues have different susceptibility to vibration. Further studies will be needed to deepen our knowledge of physiological adaptations to vibration and develop customized WBV protocols to improve and preserve cognitive and motor functions.

A Signature of Exaggerated Adipose Tissue Dysfunction in Type 2 Diabetes Is Linked to Low Plasma Adiponectin and Increased Transcriptional Activation of Proteasomal Degradation in Muscle.

Insulin resistance in skeletal muscle in type 2 diabetes (T2D) is characterized by more pronounced metabolic and molecular defects than in obesity per se. There is increasing evidence that adipose tissue dysfunction contributes to obesity-induced insulin resistance in skeletal muscle. Here, we used an unbiased approach to examine if adipose tissue dysfunction is exaggerated in T2D and linked to diabetes-related mechanisms of insulin resistance in skeletal muscle. Transcriptional profiling and biological pathways analysis were performed in subcutaneous adipose tissue (SAT) and skeletal muscle biopsies from 17 patients with T2D and 19 glucose-tolerant, age and weight-matched obese controls. Findings were validated by qRT-PCR and western blotting of selected genes and proteins. Patients with T2D were more insulin resistant and had lower plasma adiponectin than obese controls. Transcriptional profiling showed downregulation of genes involved in mitochondrial oxidative phosphorylation and the tricarboxylic-acid cycle and increased expression of extracellular matrix (ECM) genes in SAT in T2D, whereas genes involved in proteasomal degradation were upregulated in the skeletal muscle in T2D. qRT-PCR confirmed most of these findings and showed lower expression of adiponectin in SAT and higher expression of myostatin in muscle in T2D. Interestingly, muscle expression of proteasomal genes correlated positively with SAT expression of ECM genes but inversely with the expression of ADIPOQ in SAT and plasma adiponectin. Protein content of proteasomal subunits and major ubiquitin ligases were unaltered in the skeletal muscle of patients with T2D. A transcriptional signature of exaggerated adipose tissue dysfunction in T2D, compared with obesity alone, is linked to low plasma adiponectin and increased transcriptional activation of proteasomal degradation in skeletal muscle.

Development of Myostatin Inhibitory d-Peptides to Enhance the Potency, Increasing Skeletal Muscle Mass in Mice.

Myostatin is a key negative regulator of skeletal muscle growth, and myostatin inhibitors are attractive tools for the treatment of muscular atrophy. Previously, we reported a series of 14-29-mer peptide myostatin inhibitors, including a potent derivative, MIPE-1686, a 16-mer N-terminal-free l-peptide with three unnatural amino acids and a propensity to form β-sheets. However, the in vivo biological stability of MIPE-1686 is a concern for its development as a drug. In the present study, to develop a more stable myostatin inhibitory d-peptide (MID), we synthesized various retro-inverso versions of a 16-mer peptide. Among these, an arginine-containing derivative, MID-35, shows a potent and equivalent in vitro myostatin inhibitory activity equivalent to that of MIPE-1686 and considerable stability against biodegradation. The in vivo potency of MID-35 to increase the tibialis anterior muscle mass in mice is significantly enhanced over that of MIPE-1686, and MID-35 can serve as a new entity for the prolonged inactivation of myostatin in skeletal muscle.

Regulation of Myostatin on the Growth and Development of Skeletal Muscle.

Myostatin (MSTN), a member of the transforming growth factor-β superfamily, can negatively regulate the growth and development of skeletal muscle by autocrine or paracrine signaling. Mutation of the myostatin gene under artificial or natural conditions can lead to a significant increase in muscle quality and produce a double-muscle phenotype. Here, we review the similarities and differences between myostatin and other members of the transforming growth factor-β superfamily and the mechanisms of myostatin self-regulation. In addition, we focus extensively on the regulation of myostatin functions involved in myogenic differentiation, myofiber type conversion, and skeletal muscle protein synthesis and degradation. Also, we summarize the induction of reactive oxygen species generation and oxidative stress by myostatin in skeletal muscle. This review of recent insights into the function of myostatin will provide reference information for future studies of myostatin-regulated skeletal muscle formation and may have relevance to agricultural fields of study.

A new therapeutic effect of fenofibrate in Duchenne muscular dystrophy: The promotion of myostatin degradation.

Duchenne muscular dystrophy (DMD) is a degenerative muscle disease with no effective drug treatment. This study investigated the positive effects of fenofibrate on dystrophic muscles. Myostatin expression in serum and muscle tissue from patients with Duchenne muscular dystrophy and mdx mice were tested. Primary myoblasts isolated from mdx mice were challenged with an inflammatory stimulus and treated with fenofibrate. In animal experiments, 6-week-old male mdx mice were treated with fenofibrate (100 mg kg-1 ) administered orally once per day for 6weeks. Effects of fenofibrate were evaluated by tests of muscle function plus histology and biochemical analyses of serum. Expression of myostatin, MuRF1, and atrogin-1 in skeletal muscle was evaluated by western blotting and real-time PCR. Total and oxidative myosin heavy chain (MHC) were assessed via immunofluorescence. Expression of myostatin protein was increased in dystrophic muscle of patients with Duchenne muscular dystrophy and mdx mice. Fenofibrate enhanced myofibre differentiation by down-regulating the expression of myostatin protein but not mRNA in primary myoblasts of mdx mice. Fenofibrate significantly improved muscle function while ameliorating muscle damage in mdx mice. These benefits were accompanied by an anti-inflammatory effect. Fenofibrate treatment returned myofibre function by inhibiting the expressions of myostatin, MuRF1, and atrogin-1 protein in the gastrocnemius muscle and diaphragm, while leaving the mRNA level of myostatin unaffected. Fenofibrate substantially slows muscle dystrophy by promoting the degradation of myostatin protein, which may indicate a new therapeutic focus for patients with Duchenne muscular dystrophy.

Summer season induced heat stress associated changes on meat production and quality characteristics, myostatin and HSP70 gene expression patterns in indigenous goat

The study was conducted to assess the effect of heat stress on the meat production and quality variables in indigenous Malabari breed goats. The study was conducted during 45 days using twelve 10 months to one year old Malabari goats. The goats were randomly allocated into two groups: MC (n = 6; Malabari control) and MHS (n = 6; Malabari Heat stress). The MC group animals were housed inside the shed without exposure to outside environment while the MHS group animals were exposed to summer heat stress by keeping them outside the shed from 10:00 h to 16:00 h. At the end of the study, animals were slaughtered and their meat characteristics were assessed. The findings from the study revealed that heat stress caused significant reduction in live weight (P < 0.05), pre-slaughter weight (P < 0.01), hot carcass weight (P < 0.05), loin eye area (LEA) (P < 0.01), and fat score (P < 0.01). Fore saddle is the only primal cut which was significantly (P < 0.05) lower in weight in MHS as compared to MC group. Further, meat quality variables such as ultimate meat pH, water holding capacity (WHC) and shear force significantly (P < 0.01) increased during heat stress. Among the sensory characteristics, appearance (P < 0.01) and flavour (P < 0.05) reduced significantly in MHS group. However, plasma leptin level was significantly (P < 0.01) higher in MHS group. In addition, the skeletal muscle myostatin gene expression pattern was significantly (P < 0.05) lower while HSP70 gene expression was significantly (P < 0.05) higher in MHS as compared to MC group. Thus, it may be concluded from the study that indigenous Malabari goats possessed the inherent ability to maintain meat production by overcoming the adverse effects of heat stress. However, the severity of heat stress was reflected on the meat quality variables in this breed.

Skeletal muscle myostatin gene expression and sarcopenia in overweight and obese middle‐aged and older adults

BackgroundMyostatin (MSTN) is a key negative regulator of muscle mass in humans and animals, having direct and indirect influences on molecular regulators of atrophy and hypertrophy, thus potentially impacting fitness and physical function. We have shown that myostatin is elevated in conditions of chronic disability (e.g. paretic limb of stroke). Our hypothesis is that myostatin would be elevated in older adults with sarcopenia. The purpose of this study was to examine the role of skeletal muscle myostatin in sarcopenia.MethodsSixty-four overweight to obese aged 45–81 years underwent a maximal aerobic capacity (VO2max) test, dual-energy X-ray absorptiometry (DXA) scan to determine appendicular lean tissue (ALM), and vastus lateralis muscle biopsy to determine myostatin mRNA expression by quantitative real time PCR (Q-RT-PCR). Rates of sarcopenia were determined using (ALM/BMI), and sarcopenia was defined as <0.789 in men and <0.512 in women. Subjects had low fitness (VO2max: 22.7 ± 0.7 mL/kg/min) and on average 40.9 ± 1% body fat.ResultsThe prevalence of sarcopenia in this cohort was 16%. BMI, % body fat, and fat mass were higher in adults with sarcopenia than those without sarcopenia (all P < 0.001). Myostatin mRNA expression was lower in those without sarcopenia than those with sarcopenia (P < 0.05) and higher in men than women (P < 0.001). Myostatin expression was associated with BMI (r = 0.36, P < 0.01) and mid-thigh intramuscular fat (r = 0.29, P < 0.05).ConclusionGiven that myostatin is important in muscle atrophy, fat accumulation, and sarcopenia, further work could address its implication in other aging cohorts of disability and chronic disease.

Ganoderma lucidum Induces Myogenesis Markers to Avert Damage to Skeletal Muscles in Rats Exposed to Hypobaric Hypoxia.

Jatwani, Arti, and Rajkumar Tulsawani. Ganoderma lucidum induces myogenesis markers to avert damage to skeletal muscles in rats exposed to hypobaric hypoxia. High Alt Med Biol. 24:287-295, 2023. Background: Hypobaric hypoxia (HH) has been reported to induce skeletal muscle loss and impair myogenesis. Aqueous extract of G. lucidum (AqGL) contains bioactive metabolites attributed to various pharmacological effects. In this study, protective effect of AqGL in ameliorating muscle mass loss following acute HH has been reported. Materials and Methods: Male Sprague-Dawley rats were divided into following five groups of six rats in each group: unexposed control (Group 1), 6 hours of HH exposure (Group 2), 6 hours of HH exposure+AqGL extract 50 mg/kg body weight (BW) (Group 3), 6 hours of HH exposure+AqGL extract 100 mg/kg BW (Group 4), and 6 hours of HH exposure+AqGL extract 200 mg/kg BW (Group 5). Experimental animals from all groups, except Group, 1 were exposed to HH, simulated altitude of 25,000 ft for 6 hours. After exposure period, gastrocnemius muscle was collected, weighed, and morphological, biochemical, and molecular markers were analyzed. Results: HH-exposed rat muscle showed significant (p < 0.05) increase in oxidative stress markers (reactive oxygen species & malondialdehyde), which was concomitant with decrease in its mass compared to controls. AqGL treatment significantly (p < 0.05) prevented muscle oxidative stress, restored reduced glutathione content, reduced protein carbonyl content and advanced oxidation protein product, and restored muscle mass loss at effective dose of 100 mg/kg BW. Furthermore, AqGL supplementation enhanced Myf5 (p < 0.01), MyoD (p < 0.01), MyoG (p < 0.05), and Mrf4 (nonsignificantly), brain-derived neurotrophic factor (p < 0.01), and interleukin 6 (p < 0.01) expression along with restoration of tumor necrosis factor alpha (p < 0.001) and myostatin (p < 0.05) in hypoxia-exposed muscle, evidencing induction of myogenesis markers. Moreover, histological analysis showed increased myocyte number; nuclei shifted toward the periphery in the treatment group supporting muscle regeneration. Conclusion: AqGL supplementation attenuates muscle mass loss by preventing oxidative stress and inducing modulation in myogenesis markers under HH environment.