Disease relevance of GDF8

• These results suggest that GRB14, GPD1, and GDF8 are weight loss-responsive genes in skeletal muscle and that the observed transcriptional modulation of these would be expected to improve insulin signaling, decrease triglyceride synthesis, and increase muscle mass, respectively, with weight loss [1].
• However, failure to reduce myostatin expression may play a role in limiting RL-induced hypertrophy in OF [2].
• Myostatin is regarded as a good drug target since therapeutics that modulate skeletal muscle growth would be useful for disease conditions such as muscular dystrophy, sarcopenia, cachexia and even diabetes [3].
• Although myostatin is physiologically more related to muscle mass through possible effects of hyperplasia and hypertrophy than it is to strength, only two estimated muscle cross-sectional areas were marginally linked (LOD 1.06 and 1.07, P = 0.01) with marker D2S118 near GDF8 (2q32.2) [4].
• However, it is not known whether myostatin regulates skeletal muscle growth in adult men and whether increased myostatin expression contributes to wasting in chronic illness [5].

Psychiatry related information on GDF8

• Results indicate that increases in bone strength with exercise are greater in myostatin-deficient mice than in wildtype mice, suggesting that the combination of increased muscle mass and physical activity has a greater effect on bone strength than either increased muscle mass or intense exercise alone [6].
• Manipulations of myostatin signalling may be useful for agriculture applications, treatment of muscle diseases, inhibition of muscle atrophy and last but not least as life style drugs in antiaging therapies or manipulations of the muscle to fat ratio [7].

High impact information on GDF8

• We herein demonstrate that the GDF8 allele of Texel sheep is characterized by a G to A transition in the 3' UTR that creates a target site for mir1 and mir206, microRNAs (miRNAs) that are highly expressed in skeletal muscle [8].
• We mapped a quantitative trait locus with a major effect on muscle mass to chromosome 2 and subsequently fine-mapped it to a chromosome interval encompassing the myostatin (GDF8) gene [8].
• This causes translational inhibition of the myostatin gene and hence contributes to the muscular hypertrophy of Texel sheep [8].
• A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle [9].
• During early stages of embryogenesis, GDF-8 expression is restricted to the myotome compartment of developing somites [10].

Chemical compound and disease context of GDF8

• Rats that received dexamethasone showed significant body and muscle weight loss accompanied by an increase in intramuscular myostatin expression, compared with their saline-treated controls [11].
• We hypothesized that glutamine effect on reversal of GC-induced muscle atrophy is mediated in part by suppression of myostatin [11].

Biological context of GDF8

• Linkage patterns were observed between knee extension and flexion peak torque with markers D2S118 (GDF8), D6S1051 (CDKN1A), and D11S4138 (MYOD1), and a maximum LOD score of 2.63 (P = 0.0002) was observed with D2S118 [4].
• Functional studies show that FLRG inhibits myostatin activity in a reporter gene assay [12].
• Moreover, we observed a decrease in wingless-type MMTV integration site family member 10B and an upregulation of growth differentiation factor 8 expression, both being independent of PPARG activation [13].
• Impact of resistance loading on myostatin expression and cell cycle regulation in young and older men and women [2].
• The myostatin gene comprises three exons and two introns, maps to chromosomal region 2q33.2, has three putative transcription initiation sites, and is transcribed as a 3.1-kb mRNA species that encodes a 375-aa precursor protein [5].

Anatomical context of GDF8

• GRB14, GPD1, and GDF8 as potential network collaborators in weight loss-induced improvements in insulin action in human skeletal muscle [1].
• Myostatin inhibits myoblast proliferation and differentiation in developing muscle [2].
• RESULTS: Human placentas were shown to express myostatin protein, with a significantly lower expression in term samples compared with samples collected in preterm samples [14].
• In this investigation, we show that myostatin, a skeletal muscle-specific inhibitor of growth and differentiation is expressed and translated in the cultured RMS cell line, RD [15].
• Myostatin treatment resulted in a reduction in both myotube number and size in vitro, as well as a loss in body mass in vivo [16].

Associations of GDF8 with chemical compounds

• Myostatin is expressed uniquely in the human skeletal muscle as a 26-kDa mature glycoprotein (myostatin-immunoreactive protein) and secreted into the plasma [5].
• Myostatin is a human placental product that regulates glucose uptake [14].
• Myostatin treatment of human term placental explants resulted in an increase in deoxyglucose uptake compared with controls [14].
• Myostatin Induces Cyclin D1 Degradation to Cause Cell Cycle Arrest through a Phosphatidylinositol 3-Kinase/AKT/GSK-3beta Pathway and Is Antagonized by Insulin-like Growth Factor 1 [17].
• We further showed that phosphorylation at threonine 286 by GSK-3beta was required for myostatin-stimulated cyclin D1 nuclear export and degradation [17].
• Our results demonstrate that activin binding and neutralization are mediated primarily by FSD2, whereas myostatin binding is more dependent on FSD1, such that deletion of FSD2 or adding an extra FSD1 in place of FSD2 creates myostatin antagonists with vastly reduced activin antagonism [18].

Physical interactions of GDF8

• hSGT interacts with the N-terminal region of myostatin [19].
• Mutagenesis of highly conserved FoxO or SMAD binding sites significantly decreased myostatin promoter activity, and binding assays showed that both FoxO1 and SMADs bind to their respective sites in the myostatin promoter [20].
• Myostatin is increased and complexes with amyloid-beta within sporadic inclusion-body myositis muscle fibers [21].

Regulatory relationships of GDF8

• In this study, we demonstrated that myostatin down-regulates Cdk4 activity via promotion of cyclin D1 degradation [17].
• CONCLUSIONS: Resistance training and/or increased glucocorticoid receptor expression appears to up-regulate myostatin mRNA expression [22].
• Concordantly the myostatin promoter was repressed by NOR-1 expression [23].
• These results suggest that the myostatin signal transduction pathway is regulated by Smad7 through a negative feedback mechanism [24].
• Here we examined the role of FoxO1 and SMAD transcription factors in regulating myostatin gene expression and myoblast differentiation in C(2)C(12) myotubes in vitro [20].
• Myostatin induced phosphorylation of Smad3 in hMSCs; knockdown of Smad3 by RNAi or inhibition of its upstream kinase by an Alk5 inhibitor blocked the inhibitory effect of myostatin on adipogenesis in hMSCs, implying an important role of Smad3 activation in this event [25].

Other interactions of GDF8

• Muscle mass and myofibrillar protein synthesis rates among eight older men did not correlate with either IGF-1 or myostatin mRNA levels [26].
• These findings suggest that hSGT may play a role in the regulation of myostatin secretion and activation [19].
• Herein, we report the identification of a myostatin-associated protein hSGT (human small glutamine-rich tetratricopeptide repeat-containing protein) by using a yeast two-hybrid system [19].
• Activins, myostatin and related TGF-beta family members as novel therapeutic targets for endocrine, metabolic and immune disorders [3].
• Here we describe a potent myostatin inhibitor, a soluble form of the activin type IIB receptor (ACVR2B), which can cause dramatic increases in muscle mass (up to 60% in 2 weeks) when injected into wild-type mice [27].

Analytical, diagnostic and therapeutic context of GDF8

• The physical interaction between hSGT and myostatin was further confirmed by pull-down and co-immunoprecipitation experiments [19].
• To determine the biological function of GDF-8, we disrupted the GDF-8 gene by gene targeting in mice [10].
• MATERIALS AND METHODS: Myostatin protein and mRNA were measured using Western immunoblotting and real-time PCR, respectively [14].
• In the present work we quantified by real-time RT-PCR myostatin expression in muscle biopsies of a group of morbidly obese patients before and after weight loss obtained by biliopancreatic diversion (BPD) [28].
• Little is known about myostatin function in muscle growth regulation in humans and in particular during caloric restriction [28].

References