Recent genetic discoveries in osteoporosis, sarcopenia and obesity [Review]

Urano, Tomohiko; Inoue, Satoshi

doi:10.1507/endocrj.ej15-0154

Cited by 59 publications

(40 citation statements)

References 105 publications

(75 reference statements)

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“…There are numerous causes of sarcopenia including anorexia, inflammation, hypogonadism, lack of activity, hypovitaminosis D, motoneuron loss, insulin resistance, poor blood flow to muscle, mitochondrial dysfunction, and genetic causes …”

mentioning

confidence: 99%

“…There are numerous causes of sarcopenia including anorexia, 47 inflammation, 48 hypogonadism, 49 lack of activity, 50 hypovitaminosis D, 51 motoneuron loss, 52,53 insulin resistance, 54 poor blood flow to muscle, 55 mitochondrial dysfunction, 56 and genetic causes. 57 The established treatment for sarcopenia is resistance exercise. [58][59][60] It appears that sarcopenia is always responsive to resistance exercise.…”

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confidence: 99%

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Welcome to the ICD‐10 code for sarcopenia

Anker

Morley

Haehling

2016

J cachexia sarcopenia muscle

704

414

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mentioning

confidence: 99%

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confidence: 99%

Welcome to the ICD‐10 code for sarcopenia

Anker

Morley

Haehling

2016

J cachexia sarcopenia muscle

704

414

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“…SO has strong genetic components that are linked to the risk for type2 diabetes and atherosclerosis (5)(6)(7)(8)(9). The advent of human genome project has provided an excellent opportunity for the discovery of novel disease genes and their cognate pathways.…”

Section: Introductionmentioning

confidence: 99%

Dyrk1b is a key Regulatory Kinase Integrating Fgf, Shh and mTORC1 signaling in Skeletal Muscle Development and Homeostasis

Bhat

Narayanan

Fathzadeh

et al. 2020

Preprint

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Dyrk1b: Dual-specificity Tyrosine-regulated kinase 1B SO: sarcopenic obesity MetS: metabolic syndrome myoD1: myoblast determination protein 1 Fgf: Fibroblast growth factor Shh: Sonic Hedgehog mTORC1: mechanistic target of rapamycin C1 4e-bp1: Eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 ABSTRACTThe advent of human genetics has provided unprecedented opportunities for discovery of novel disease pathways. Mutations in DYRK1B have been associated with metabolic syndrome and sarcopenic obesity in humans, underscoring the critical role of the encoded protein in skeletal muscle development and homeostasis. By the novel creation of Dyrk1b knockout zebrafish models we demonstrate that Dyrk1b kinase activity is critical for specification of the paraxial myoD. Mechanistically, Dyrk1b mediates and amplifies Fgf signaling in the paraxial domain by the transcriptional suppression of its negative feedback inhibitor sprouty1. In the adaxial myoD domain, Dyrk1b amplifies Shh signaling and partially rescues defects caused by its disruption. The investigations of C2C12 terminal differentiation revealed that Dyrk1b also plays a critical role in myofiber fusion. Combined biochemical and proteomic analysis of C2C12 myoblasts undergoing differentiation showed that Dyrk1b kinase activation is induced by shh inhibition, and triggers differentiation by inhibiting mTOR, subsequent upregulation of 4e-bp1 and induction of autophagy. In conclusion, we demonstrate that Dyrk1b plays a critical role in sustaining myocyte specification and differentiation by integrating Fgf, Shh and mTORC1 signaling pathways. determination, inherited metabolic syndrome. E lateral views, F-G dorsal views, H and I are cross-sections at regions indicated by red lines on G. Red asterisks on F and G indicate the unstained axial domain. Red asterisks on I denote somites, red arrow denotes notochord, NT=neural tube. J,K are group shots of zebrafish embryos stained with anti-sense and the control sense probe. L. Schematic diagram of the dyrk1b locus in the zebrafish genome. Boxes indicate the exons (not drawn to scale). The dotted lines from second exon indicate the translation start site (in red). Guide RNA is highlighted in yellow and PAM region in green. wildtype and dyrk1b+/-sequence are shown, 7bp insertion induced by CRISPR/Cas9 is highlighted in blue. M Schematic showing Dyrk1b CRISPR/Cas9 injection and transmission of induced mutation. N T7 assay with one band for Wildtype and two bands for dyrk1b+/-, indicating the heteroduplex formed by CRISPR/Cas9 activity. O. Sanger sequencing images of amplified segments of wildtype and dyrk1b+/-, demonstrating the site of 7bp insertion (red arrow) and the ensuing frame shift. P. dyrk1b mRNA expression levels (mean + s.e.m) in the wildtype and Dyrk1b+/-zebrafish embryo at 24hpf (*** p≤ 0.001, Students ttest, 2 tailed, n=30 pooled embryos).

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“…A continuous distribution of the trait and data obtained from 55 animal models 5-7 indicates a polygenic causality. However, thus far, genome-wide association 56 studies (GWAS) have implicated fewer than a dozen genes, explaining a small fraction of this 57 heritability 8; 9 . Limited sample size in early studies 10-14 and the effects of confounders such as 58 subject age 8 , size of the skeleton and lean mass components (non-fat organs and tissues, 59 heterogeneity of muscle fibers) have hindered detection of genes.…”

Section: Introduction 45mentioning

confidence: 99%

Genome-wide associations reveal human-mouse genetic convergence and modifiers of myogenesis,CPNE1andSTC2

Cordero

Gonzales²,

Parker

et al. 2018

Preprint

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29Muscle bulk in adult healthy humans is highly variable even after accounting for height, age and 30 sex. Low muscle mass, due to fewer and/or smaller constituent muscle fibers, would exacerbate 31 the impact of muscle loss occurring in aging or disease. Genetic variability substantially influences 32 muscle mass differences, but causative genes remain largely unknown. In a genome-wide 33 association study (GWAS) on appendicular lean mass (ALM) in a population of 85,750 middle-age 34 (38-49 years) individuals from the UK Biobank (UKB) we found 182 loci associated with ALM 35 (P<5x10 -8 ). We replicated associations for 78% of these loci (P<5x10 -8 ) with ALM in a population of 36 181,862 elderly (60-74 years) individuals from UKB. We also conducted a GWAS on hindlimb 37 skeletal muscle mass of 1,867 mice from an advanced intercross between two inbred strains (LG/J 38 and SM/J) which identified 23 quantitative trait loci. 38 positional candidates distributed across 5 39 loci overlapped between the two species. In vitro studies of positional candidates confirmed 40 CPNE1 and STC2 as modifiers of myogenesis. Collectively, these findings shed light on the 41 genetics of muscle mass variability in humans and identify targets for the development of 42 interventions for treatment of muscle loss. The overlapping results between humans and the 43 mouse model GWAS point to shared genetic mechanisms across species. 44

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Recent genetic discoveries in osteoporosis, sarcopenia and obesity [Review]

Cited by 59 publications

References 105 publications

Welcome to the ICD‐10 code for sarcopenia

Welcome to the ICD‐10 code for sarcopenia

Dyrk1b is a key Regulatory Kinase Integrating Fgf, Shh and mTORC1 signaling in Skeletal Muscle Development and Homeostasis

Genome-wide associations reveal human-mouse genetic convergence and modifiers of myogenesis,CPNE1andSTC2

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