Deciphering Myostatin’s Regulatory, Metabolic, and Developmental Influence in Skeletal Diseases

Omosule, Catherine L.; Phillips, Charlotte L.

doi:10.3389/fgene.2021.662908

Cited by 14 publications

(9 citation statements)

References 116 publications

(216 reference statements)

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“…Hence, our data suggest that, in the absence of comorbidities, myostatin knockout (GDF8 -/- ), although enhanced muscle mass, moderately influences bone phenotype in adult mice. However, other studies in mouse models of osteoporosis, osteoarthritis, osteogenesis imperfecta, muscular dystrophy, and diabetes show that pharmacological inhibition of myostatin improves muscle and bone properties to a greater extend 60 . Myostatin inhibition also ameliorates obesity-induced bone loss and trabecular architecture deterioration in rats 61 .…”

Section: Discussionmentioning

confidence: 96%

Biomechanical Stimulation of Muscles Influences Bone Phenotype by Modulating Myokine Secretion

Kumar

Barnett

Kalaitzoglou

et al. 2022

Preprint

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Diabetes is a chronic metabolic disorder that affects 422 million people worldwide and can lead to diabetic myopathy and bone diseases. The etiology of musculoskeletal complications in diabetes and the interplay between the muscular and osseous systems are poorly understood. Exercise training promises to prevent diabetic myopathy and diabetic bone disease and offer protective effects on muscle and bone. Although the muscle-bone interaction is largely biomechanical, the muscle secretome, specifically the myokines, has significant implications for bone biology. Here, we have developed an in vitro model to elucidate the effects of mechanical strain on myokine secretion and its impact on bone metabolism decoupled from physical stimuli. We developed modular bone constructs using crosslinked gelatin hydrogels which facilitated osteogenic differentiation of osteoprogenitor cells. Then muscle constructs were made from fibrin hydrogel, which enabled myoblast differentiation and formed mature myotubes. We investigated the myokine expression by the muscle constructs under strain regimens replicating endurance (END) and high-intensity interval training (HIIT) in hyperglycemic conditions. In monocultures, both regimens induced higher expression of Il15 and Igf1, while END supported more myoblasts differentiation and myotube maturation than HIIT. When cocultured with bone constructs, the HIIT regimen increased Glut4 expression in muscle contructs that END supporting higher glucose uptake. Likewise, the muscle constructs under the HIIT regimen promoted a healthier and matured bone phenotype than END. Interestingly, under static conditions, myostatin (Mstn) expression was significantly downregulated in muscle constructs cocultured with bone constructs compared to monocultures. Our in vivo analysis of the role of myostatin on bone structure and function also showed that myostatin knockout (GDF8-/-) enhanced muscle mass and moderately influenced bone phenotype in adult mice. Together, our in vitro coculture system allowed orthogonal manipulation of mechanical strain on muscle constructs while facilitating biochemical crosstalk between bone and muscle constructs. Such systems can provide an individualized microenvironment and allow decoupled biomechanical manipulation, which is unachievable using traditional models. In the long-term, these in-vitro systems will help identify molecular targets and develop engineered therapies for diabetic bone disease.

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Section: Discussionmentioning

confidence: 96%

Biomechanical Stimulation of Muscles Influences Bone Phenotype by Modulating Myokine Secretion

Kumar

Barnett

Kalaitzoglou

et al. 2022

Preprint

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“…[332][333][334] Besides sarcopenia and musculoskeletal diseases, alterations in myostatin are also found in the pathophysiology of myocardial infarctions, inflammation, IR, diabetes, cachexia and cancer. 335 Serum myostatin levels were significantly higher in HCC patients as compared to healthy controls and showed a positive correlation with sarcopenia. 282 Thus role of myostatin in NAFLD and NASH related HCC warrants further investigation.…”

Section: Myostatinmentioning

confidence: 89%

“…In aged patients high myostatin and IR coexists with NAFLD and sarcopenia thereby connecting the three vital metabolic organs namely liver, adipose tissue, and skeletal muscle 332–334 . Besides sarcopenia and musculoskeletal diseases, alterations in myostatin are also found in the pathophysiology of myocardial infarctions, inflammation, IR, diabetes, cachexia and cancer 335 . Serum myostatin levels were significantly higher in HCC patients as compared to healthy controls and showed a positive correlation with sarcopenia 282 .…”

Section: Myokinesmentioning

confidence: 98%

Contribution of organokines in the development of NAFLD/NASH associated hepatocellular carcinoma

Vachher

Bansal

Kumar

et al. 2022

J of Cellular Biochemistry

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Globally the incidence of hepatocellular carcinoma (HCC) is on an upsurge. Evidence is accumulating that liver disorders like nonalcoholic fatty liver disease (NAFLD) and its more progressive form nonalcoholic steatohepatitis (NASH) are associated with increased risk of developing HCC. NAFLD has a prevalence of about 25% and 50%–90% in obese population. With the growing burden of obesity epidemic worldwide, HCC presents a major healthcare burden. While cirrhosis is one of the major risk factors of HCC, available literature suggests that NAFLD/NASH associated HCC also develops in minimum or noncirrhotic livers. Therefore, there is an urgent need to understand the pathogenesis and risk factors associated with NAFLD and NASH related HCC that would help in early diagnosis and favorable prognosis of HCC secondary to NAFLD. Adipokines, hepatokines and myokines are factors secreted by adipocytes, hepatocytes and myocytes, respectively, playing essential roles in cellular homeostasis, energy balance and metabolism with autocrine, paracrine and endocrine effects. In this review, we endeavor to focus on the role of these organokines in the pathogenesis of NAFLD/NASH and its progression to HCC to augment the understanding of the factors stimulating hepatocytes to acquire a malignant phenotype. This shall aid in the development of novel therapeutic strategies and tools for early diagnosis of NAFLD/NASH and HCC.

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“…Myostatin-null mice (MSTN−/−) exhibit skeletal muscle fiber hyperplasia and hypertrophy, whereas myostatin deficiency in larger mammals, such as sheep and pigs, can result in muscle fiber hyperplasia. Myostatin's impact extends beyond muscles, with alterations in myostatin present in the pathophysiology of myocardial infarctions, inflammation, insulin resistance, diabetes, aging, cancer cachexia, and musculoskeletal disease [31].…”

Section: Discussionmentioning

confidence: 99%

Genetic Variations and Haplotypic Diversity in the Myostatin Gene of Different Cattle Breeds in Russia

Коновалова

Romanenkova

Zimina

et al. 2021

Animals

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The myostatin gene (MSTN) in cattle has a number of polymorphisms associated with increased muscle mass. The aim of the current study was to determine the haplotype frequencies of F94L and nt821(del11) MSTN polymorphisms among cattle bred for meat in Russia, using DNA analysis. Using the earlier created test systems based on the AS-PCR and PCR-RFLP methods, six populations of Aberdeen Angus (n = 684), two populations of Limousin (n = 54), one population of Simmental (n = 55), and one population of Belgian Blue (n = 137) belonging to Russian farms were genotyped on nt821(del11) and F94L MSTN polymorphisms. The animal carriers of the mutant allele of nt821(del11) MSTN associated with the double-muscling genetic defect were found in one Aberdeen Angus population at a frequency of 2.18%, but were not found in the Limousin and Simmental populations. However, 100% of the Belgian Blue population were heterozygous carriers of nt821(del11) MSTN. The frequencies of the A allele F94L MSTN desirable for productivity traits in the Limousin populations were the highest and accounted for 0.97 and 1 in populations one and two, while in the Aberdeen Angus, Simmental, and Belgian Blue populations, these figures were considerably lower at 0.04–0.08, depending on the population. The obtained data show the high genetic potential of Russian beef cattle, and facilitate an improvement in meat productivity by preserving the health of animals.

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Deciphering Myostatin’s Regulatory, Metabolic, and Developmental Influence in Skeletal Diseases

Cited by 14 publications

References 116 publications

Biomechanical Stimulation of Muscles Influences Bone Phenotype by Modulating Myokine Secretion

Biomechanical Stimulation of Muscles Influences Bone Phenotype by Modulating Myokine Secretion

Contribution of organokines in the development of NAFLD/NASH associated hepatocellular carcinoma

Genetic Variations and Haplotypic Diversity in the Myostatin Gene of Different Cattle Breeds in Russia

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