Building muscle, browning fat and preventing obesity by inhibiting myostatin

Robert & Arlene Kogod Center on Aging, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Diabetologia (Impact Factor: 6.67). 11/2011; 55(1):13-7. DOI: 10.1007/s00125-011-2361-8
Source: PubMed


The obesity epidemic is an overwhelming global health concern. Interventions to improve body weight and composition aim to restore balance between nutrient intake and energy expenditure. Myostatin, a powerful negative regulator of skeletal muscle mass, has emerged as a potential therapeutic target for obesity and type 2 diabetes mellitus because of the prominent role skeletal muscle plays in metabolic rate and insulin-mediated glucose disposal. In fact, inhibition of myostatin by genetic manipulation or pharmacological means leads to a hypermuscular and very lean build in mice. The resistance of myostatin-null mice to diet-induced obesity, fat mass accumulation and metabolic dysfunction has been presumed to be a result of their large skeletal muscle mass; however, in this issue of Diabetologia, Zhang et al. (doi: 10.1007/s00125-011-2304-4 ) provide evidence that myostatin inhibition also significantly impacts the phenotype of white adipose tissue (WAT). The authors reveal elevated expression of key metabolic genes of fatty acid transport and oxidation and, intriguingly, the presence of brown adipose tissue-like cells in WAT of myostatin-null mice. They also show that pharmacological inhibition of myostatin replicates several of the protective benefits conveyed by its genetic inactivation. Herein, these data, areas in need of further investigation and the evidence that implicates myostatin as a target for obesity and type 2 diabetes mellitus are discussed.


Available from: Nathan K LeBrasseur, Feb 11, 2014
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    • "A recent animal study showed that Myostatin plays an important role in myogenic and adipogenic cells, and that the gene had different roles in the adipogenesis of pig adipose-derived stem cells (ADSCs) and muscle satellite cells (MSCs)29. Another animal study showed that the resistance of Myostatin-null mice to diet-induced obesity, fat mass accumulation and metabolic dysfunction is not only a result of their large skeletal muscle mass, but it may also be a result of significant changes in the phenotype of white adipose tissue (WAT)30. Based on this research, we focused our study on the relationship between Myostatin and obesity-related phenotype in humans and we found that rs3791783 is significantly correlated with the trunk fat mss in the Chinese young males, which indicated that apart from the polymorphism itself is the functionally relevant locus or the polymorphism is in linkage disequilibrium with other functional variants in closely situated genes of Myostatin gene. "
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    ABSTRACT: Myostatin gene is a member of the transforming growth factor-β (TGF-β) family that negatively regulates skeletal muscle growth. Genetic polymorphisms in Myostatin were found to be associated with the peak bone mineral density (BMD) in Chinese women. The purpose of this study was to investigate whether myostatin played a role in the normal variation in peak BMD, lean mass (LM), and fat mass (FM) of Chinese men. Four hundred male-offspring nuclear families of Chinese Han ethnic group were recruited. Anthropometric measurements, including the peak BMD, body LM and FM were measured using dual-energy X-ray absorptiometry (DXA). The single nucleotide polymorphisms (SNPs) studied were tag-SNPs selected by sequencing. Both rs2293284 and +2278GA were genotyped using TaqMan assay, and rs3791783 was genotyped with PCR-restriction fragment length polymorphism (RFLP) analysis. The associations of the SNPs with anthropometric variations were analyzed using the quantitative transmission disequilibrium test (QTDT). Using QTDT to detect within-family associations, neither single SNP nor haplotype was found to be associated with peak BMD at any bone site. However, rs3791783 was found to be significantly associated with fat mass of the trunk (P<0.001). Moreover, for within-family associations, haplotypes AGG, AAA, and TGG were found to be significantly associated with the trunk fat mass (all P<0.001). Our results suggest that genetic variation within myostatin may play a role in regulating the variation in fat mass in Chinese males. Additionally, the myostatin gene may be a candidate that determines body fat mass in Chinese men.
    Acta Pharmacologica Sinica 03/2012; 33(5):660-7. DOI:10.1038/aps.2012.12 · 2.91 Impact Factor
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    ABSTRACT: Body composition is related to various physiological and pathological states. Characterization of individual body components adds to understand metabolic, endocrine and genetic data on obesity and obesity-related metabolic risks, e.g. insulin resistance. The obese phenotype is multifaceted and can be characterized by measures of body fat, leg fat, liver fat and skeletal muscle mass rather than by body mass index. The contribution of either whole body fat or fat distribution or individual fat depots to insulin resistance is moderate, but liver fat has a closer association with (hepatic) insulin resistance. Although liver fat is associated with visceral fat, its effect on insulin resistance is independent of visceral adipose tissue. In contrast to abdominal fat, appendicular or leg fat is inversely related to insulin resistance. The association between 'high fat mass + low muscle mass' (i.e. 'sarcopenic adiposity') and insulin resistance deserves further investigation and also attention in daily clinical practice. In addition to cross-sectional data, longitudinal assessment of body composition during controlled under- and overfeeding of normal-weight healthy young men shows that small decreases and increases in fat mass are associated with corresponding decreases and increases in insulin secretion as well as increases and decreases in insulin sensitivity. However, even under controlled conditions, there is a high intra- and inter-individual variance in the changes of (i) body composition; (ii) the 'body composition-glucose metabolism relationship' and (iii) glucose metabolism itself. Combining individual body components with their related functional aspects (e.g. the endocrine, metabolic and inflammatory profiles) will provide a suitable basis for future definitions of a 'metabolically healthy body composition'.
    Obesity Reviews 12/2012; 13 Suppl 2(S2):6-13. DOI:10.1111/j.1467-789X.2012.01033.x · 8.00 Impact Factor
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    ABSTRACT: Myostatin (Mstn) is predominantly expressed in skeletal muscles and plays important roles in regulating muscle growth and development, as well as fat deposition. Mstn-knockout (Mstn(-/-)) mice exhibit increased muscle mass due to both hypertrophy and hyperplasia, and leaner body composition due to reduced fat mass. Here, we show that white adipose tissue (WAT) of Mstn(-/-) develops characteristics of brown adipose tissue (BAT) with dramatically increased expression of BAT signature genes, including Ucp1 and Pgc1α, and beige adipocyte markers Tmem26 and CD137. Strikingly, the observed browning phenotype is non-cell autonomous and is instead driven by the newly defined myokine irisin (Fndc5) secreted from Mstn(-/-) skeletal muscle. Within the muscle, Mstn(-/-) leads to increased expression of AMPK and its phosphorylation, which subsequently activates PGC1α and Fndc5. Together, our study defines a paradigm of muscle-fat crosstalk mediated by Fndc5, which is up-regulated and secreted from muscle to induce beige cell markers and the browning of WAT in Mstn(-/-) mice. These results suggest that targeting muscle Mstn and its downstream signaling represents a therapeutic approach to treat obesity and type 2 diabetes.-Shan, T., Liang, X., Bi, P., Kuang, S. Myostatin knockout drives browning of white adipose tissue through activating the AMPK-PGC1α-Fndc5 pathway in muscle.
    The FASEB Journal 01/2013; 27(5). DOI:10.1096/fj.12-225755 · 5.04 Impact Factor
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