scholarly journals Integration of genetic colocalizations with physiological and pharmacological perturbations identifies cardiometabolic disease genes

2021 ◽  
Author(s):  
Michael J. Gloudemans ◽  
Brunilda Balliu ◽  
Daniel Nachun ◽  
Matthew G. Durrant ◽  
Erik Ingelsson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Interactions ◽  
Cardiometabolic Disease ◽  
Disease Genes ◽  
Genetic Associations ◽  
Protein Protein Interactions ◽  
Transcriptional Responses ◽  
Liver And Pancreas ◽  
Causal Genes ◽  
Upstream Regulators

AbstractBackgroundIdentification of causal genes for polygenic human diseases has been extremely challenging, and our understanding of how physiological and pharmacological stimuli modulate genetic risk at disease-associated loci is limited. Specifically, insulin resistance (IR), a common feature of cardiometabolic disease, including type 2 diabetes, obesity, and dyslipidemia, lacks well-powered GWAS, and therefore few associated loci and causal genes have been identified.ResultsHere, we perform and integrate LD-adjusted colocalization analyses across nine cardiometabolic traits combined with eQTLs and sQTLs from five metabolically relevant human tissues (subcutaneous and visceral adipose, skeletal muscle, liver, and pancreas). We identify 470 colocalized loci and prioritize 207 loci with a single colocalized gene. To elucidate upstream regulators and functional mechanisms for these genes, we integrate their transcriptional responses to 21 physiological and pharmacological cardiometabolic regulators in human adipocytes, hepatocytes, and skeletal muscle cells, and map their protein-protein interactions.ConclusionsOur use of transcriptional responses under metabolic perturbations to contextualize genetic associations from our state-of-the-art colocalization approach provides a list of likely causal genes and their upstream regulators in the context of IR-associated cardiometabolic risk.

Subcellular localization of skeletal muscle lipid droplets and PLIN family proteins OXPAT and ADRP at rest and following contraction in rat soleus muscle

2012 ◽  
Vol 302 (1) ◽  
pp. R29-R36 ◽  
Author(s):  
Rebecca E. K. MacPherson ◽  
Eric A. F. Herbst ◽  
Erica J. Reynolds ◽  
Rene Vandenboom ◽  
Brian D. Roy ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Lipid Droplet ◽  
Protein Interactions ◽  
Lipid Droplets ◽  
Droplet Surface ◽  
Protein Protein Interactions ◽  
Muscle Lipid ◽  
Droplet Distribution ◽  
Associated Proteins ◽  
Skeletal Muscle Lipid

Skeletal muscle lipid droplet-associated proteins (PLINs) are thought to regulate lipolysis through protein-protein interactions on the lipid droplet surface. In adipocytes, PLIN2 [adipocyte differentiation-related protein (ADRP)] is found only on lipid droplets, while PLIN5 (OXPAT, expressed only in oxidative tissues) is found both on and off the lipid droplet and may be recruited to lipid droplet membranes when needed. Our purpose was to determine whether PLIN5 is recruited to lipid droplets with contraction and to investigate the myocellular location and colocalization of lipid droplets, PLIN2, and PLIN5. Rat solei were isolated, and following a 30-min equilibration period, they were assigned to one of two groups: 1) 30 min of resting incubation and 2) 30 min of stimulation ( n = 10 each). Immunofluorescence microscopy was used to determine subcellular content, distribution, and colocalization of lipid droplets, PLIN2, and PLIN5. There was a main effect for lower lipid and PLIN2 content in stimulated compared with rested muscles ( P < 0.05). Lipid droplet distribution declined exponentially from the sarcolemma to the fiber center in the rested muscles ( P = 0.001, r2= 0.99) and linearly in stimulated muscles (slope = −0.0023 ± 0.0006, P < 0.001, r2= 0.93). PLIN2 distribution declined exponentially from the sarcolemma to the fiber center in both rested and stimulated muscles ( P < 0.0001, r2= 0.99 rest; P = 0.0004, r2= 0.98 stimulated), while PLIN5 distribution declined linearly (slope = −0.0085 ± 0.0009, P < 0.0001, r2= 0.94 rest; slope=−0.0078 ± 0.0010, P = 0.0003, r2= 0.91 stimulated). PLIN5-lipid droplets colocalized at rest with no difference poststimulation ( P = 0.47; rest r2= 0.55 ± 0.02, stimulated r2= 0.58 ± 0.03). PLIN2-lipid droplets colocalized at rest with no difference poststimulation ( P = 0.48; rest r2= 0.66 ± 0.02, stimulated r2= 0.65 ± 0.02). Contrary to our hypothesis, these results show that PLIN5 is not recruited to lipid droplets with contraction in isolated skeletal muscle.

scholarly journals 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Coregulators as mediators of mineralocorticoid receptor signalling diversity

2017 ◽  
Vol 234 (1) ◽  
pp. T23-T34 ◽  
Author(s):  
Peter J Fuller ◽  
Jun Yang ◽  
Morag J Young
Keyword(s):  
Protein Interactions ◽  
Mineralocorticoid Receptor ◽  
Hormone Receptors ◽  
Target Genes ◽  
Steroid Hormone Receptors ◽  
Protein Protein Interactions ◽  
Transcriptional Responses ◽  
Functional Roles ◽  
Regulatory Processes ◽  
Coregulatory Proteins

The cloning of the mineralocorticoid receptor (MR) 30 years ago was the start of a new era of research into the regulatory processes of MR signalling at target genes in the distal nephron, and subsequently in many other tissues. Nuclear receptor (NR) signalling is modified by interactions with coregulatory proteins that serve to enhance or inhibit the gene transcriptional responses. Over 400 coregulatory proteins have been described for the NR super family, many with functional roles in signalling, cellular function, physiology and pathophysiology. Relatively few coregulators have however been described for the MR although recent studies have demonstrated both ligand and/or tissue selectivity for MR-coregulator interactions. A full understanding of the cell, ligand and promoter-specific requirements for MR-coregulator signalling is an essential first step towards the design of small molecular inhibitors of these protein-protein interactions. Tissue-selective steroidal or non-steroidal modulators of the MR are also a desired therapeutic goal. Selectivity, as for other steroid hormone receptors, will probably depend on differential expression and recruitment of coregulatory proteins.

scholarly journals Protein-Protein Interactions in Skeletal Muscle Calcium Transport Regulation

2014 ◽  
Vol 106 (2) ◽  
pp. 725a
Author(s):  
Joseph M. Autry ◽  
Michael D. Schaid ◽  
Kurt C. Peterson ◽  
David D. Thomas
Keyword(s):  
Skeletal Muscle ◽  
Protein Interactions ◽  
Calcium Transport ◽  
Protein Protein Interactions ◽  
Transport Regulation ◽  
Muscle Calcium

scholarly journals Differential Contribution of Skeletal and Cardiac II-III Loop Sequences to the Assembly of Dihydropyridine-Receptor Arrays in Skeletal Muscle

2004 ◽  
Vol 15 (12) ◽  
pp. 5408-5419 ◽  
Author(s):  
Hiroaki Takekura ◽  
Cecilia Paolini ◽  
Clara Franzini-Armstrong ◽  
Gerlinde Kugler ◽  
Manfred Grabner ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Interactions ◽  
Calcium Release ◽  
Freeze Fracture ◽  
Fracture Analysis ◽  
Dihydropyridine Receptor ◽  
Protein Protein Interactions ◽  
Loop Sequence ◽  
Subunit Isoforms ◽  
Differential Contribution

The plasmalemmal dihydropyridine receptor (DHPR) is the voltage sensor in skeletal muscle excitation-contraction (e-c) coupling. It activates calcium release from the sarcoplasmic reticulum via protein–protein interactions with the ryanodine receptor (RyR). To enable this interaction, DHPRs are arranged in arrays of tetrads opposite RyRs. In the DHPR α1S subunit, the cytoplasmic loop connecting repeats II and III is a major determinant of skeletal-type e-c coupling. Whether the essential II-III loop sequence (L720-L764) also determines the skeletal-specific arrangement of DHPRs was examined in dysgenic (α1S-null) myotubes reconstituted with distinct α1 subunit isoforms and II-III loop chimeras. Parallel immunofluorescence and freeze-fracture analysis showed that α1S and chimeras containing L720-L764, all of which restored skeletal-type e-c coupling, displayed the skeletal arrangement of DHPRs in arrays of tetrads. Conversely, α1C and those chimeras with a cardiac II-III loop and cardiac e-c coupling properties were targeted into junctional membranes but failed to form tetrads. However, an α1S-based chimera with the heterologous Musca II-III loop produced tetrads but did not reconstitute skeletal muscle e-c coupling. These findings suggest an inhibitory role in tetrad formation of the cardiac II-III loop and that the organization of DHPRs in tetrads vis-à-vis the RyR is necessary but not sufficient for skeletal-type e-c coupling.

scholarly journals Leucine-enriched amino acids maintain peripheral mTOR-Rheb localization independent of myofibrillar protein synthesis and mTORC1 signaling postexercise

2020 ◽  
Vol 129 (1) ◽  
pp. 133-143 ◽  
Author(s):  
Sarkis J. Hannaian ◽  
Nathan Hodson ◽  
Sidney Abou Sawan ◽  
Michael Mazzulla ◽  
Hiroyuki Kato ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Protein Synthesis ◽  
Protein Interactions ◽  
Human Skeletal Muscle ◽  
Myofibrillar Protein ◽  
Protein Protein Interactions ◽  
Peripheral Location ◽  
Mtorc1 Signaling ◽  
Myofibrillar Protein Synthesis

This is the first study to investigate whether postexercise leucine-enriched amino acid (LEAA) ingestion elevates mTORC1 translocation and protein-protein interactions in human skeletal muscle. Here, we observed that although LEAA ingestion did not further elevate postexercise MyoPS or mTORC1 signaling compared with placebo, mTORC1 peripheral location and interaction with Rheb were maintained. This may serve to “prime” mTORC1 for subsequent anabolic stimuli.

Force, length, and Ca(2+)-troponin C affinity in skeletal muscle

1991 ◽  
Vol 261 (5) ◽  
pp. C787-C792 ◽  
Author(s):  
F. Fuchs ◽  
Y. P. Wang
Keyword(s):  
Skeletal Muscle ◽  
Protein Interactions ◽  
Muscle Fibers ◽  
Psoas Muscle ◽  
Troponin C ◽  
Force Generation ◽  
Fluorescence Probes ◽  
Protein Protein Interactions ◽  
Rabbit Psoas ◽  
Cross Bridges

On the basis of isotopic methods it has been found that force generation promotes increased Ca2+ binding to troponin C in cardiac muscle [P. Hofmann and F. Fuchs. Am. J. Physiol. 253 (Cell Physiol. 22): C541-C546, 1987] but not in skeletal muscle (J. Muscle Res. Cell Motil. 6: 477, 1985). However, studies with skinned rabbit psoas muscle fibers containing substituted fluorescent troponin C analogues indicate that force-generating cross bridges do promote increased Ca2+ binding in skeletal muscle (K. Guth and J. D. Potter. J. Biol. Chem. 262: 13627-13635, 1987). We have reexamined this question using a modified contraction-relaxation protocol in which Ca2+ binding to detergent-treated rabbit psoas fibers was measured either during steady-state force development or after relaxation was induced by one of two myosin ATPase inhibitors, vanadate or 2,3-butanedione monoxime. A standard double-isotope technique was used to measure Ca2+ binding. Another set of experiments was done in which force was reduced by releasing muscle fibers from sarcomere lengths of 2.4-2.6 microns to 1.5-1.7 microns, and bound Ca2+ was determined either before or after the release. No statistically significant effect of force generation or sarcomere length on Ca(2+)-troponin C affinity was observed. Thus the discrepancy remains between results obtained with isotopic and fluorescence methods. It is possible that in skinned fibers emission from fluorescence probes is more closely related to protein-protein interactions than to the amount of Ca2+ bound to troponin C.

scholarly journals O-GlcNAcylation is a key modulator of skeletal muscle sarcomeric morphometry associated to modulation of protein–protein interactions

2016 ◽  
Vol 1860 (9) ◽  
pp. 2017-2030 ◽  
Author(s):  
Matthias Lambert ◽  
Elodie Richard ◽  
Sophie Duban-Deweer ◽  
Frederic Krzewinski ◽  
Barbara Deracinois ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Interactions ◽  
Protein Protein Interactions

Dihydropyridine receptor-ryanodine receptor interactions in skeletal muscle excitation-contraction coupling

1995 ◽  
Vol 15 (5) ◽  
pp. 399-408 ◽  
Author(s):  
Gerhard Meissner ◽  
Xiangyang Lu
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Ryanodine Receptor ◽  
Protein Interactions ◽  
Dihydropyridine Receptor ◽  
Coupling Mechanism ◽  
Protein Protein Interactions ◽  
Release Channel ◽  
Mechanical Coupling ◽  
Subsequent Step

Much recent progress has been made in our understanding of the mechanism of sarcoplasmic reticulum Ca2+ release in skeletal muscle. Vertebrate skeletal muscle excitation-contraction (E-C) coupling is thought to occur by a “mechanical coupling”� mechanism involving protein-protein interactions that lead to activation of the sarcoplasmic reticulum (SR) ryanodine receptor (RyR)/Ca2+ release channel by the voltage-sensing transverse (T−) tubule dihydropyridine receptor (DHPR)/Ca2+ channel. In a subsequent step, the released Ca2+ amplify SR Ca2+ release by activating release channels that are not linked to the DHPR. Experiments with mutant muscle cells have indicated that skeletal muscle specific DHPR and RyR isoforms are required for skeletal muscle E-C coupling. A direct functional and structural interaction between a DHPR-derived peptide and the RyR has been described. The interaction between the DHPR and RyR may be stabilized by other proteins such as triadin (a SR junctional protein) and modulated by phosphorylation of the DHPR.

scholarly journals Skeletal muscle PLIN proteins, ATGL and CGI-58, interactions at rest and following stimulated contraction

2013 ◽  
Vol 304 (8) ◽  
pp. R644-R650 ◽  
Author(s):  
Rebecca E. K. MacPherson ◽  
Sofhia V. Ramos ◽  
Rene Vandenboom ◽  
Brian D. Roy ◽  
Sandra J. Peters
Keyword(s):  
Skeletal Muscle ◽  
Lipid Droplet ◽  
Protein Interactions ◽  
Droplet Surface ◽  
Gene Identification ◽  
Protein Protein Interactions ◽  
Muscle Lipid ◽  
Associated Proteins ◽  
Skeletal Muscle Lipid ◽  
Intramuscular Lipid

Evidence indicates that skeletal muscle lipid droplet-associated proteins (PLINs) regulate lipolysis through protein-protein interactions on the lipid droplet surface. In adipocytes, PLIN1 is thought to regulate lipolysis by directly interacting with comparative gene identification-58 (CGI-58), an activator of adipose triglyceride lipase (ATGL). Upon lipolytic stimulation, PLIN1 is phosphorylated, releasing CGI-58 to fully activate ATGL and initiate triglyceride breakdown. The absence of PLIN1 in skeletal muscle leads us to believe that other PLIN family members undertake this role. Our purpose was to examine interactions between PLIN2, PLIN3, and PLIN5, with ATGL and its coactivator CGI-58 at rest and following contraction. Isolated rat solei were incubated for 30 min at rest or during 30 min of intermittent tetanic stimulation [150-ms volleys at 60 Hz with a train rate of 20 tetani/min (25°C)] to maximally stimulate intramuscular lipid breakdown. Results show that the interaction between ATGL and CGI-58 increased 128% following contraction ( P = 0.041). Further, ATGL interacts with PLIN2, PLIN3, and PLIN5 at rest and following contraction. The PLIN2-ATGL interaction decreased significantly by 21% following stimulation ( P = 0.013). Both PLIN3 and PLIN5 coprecipitated with CGI-58 at rest and following contraction, while there was no detectable interaction between PLIN2 and CGI-58 in either condition. Therefore, our findings indicate that in skeletal muscle, during contraction-induced muscle lipolysis, ATGL and CGI-58 strongly associate and that the PLIN proteins work together to regulate lipolysis, in part, by preventing ATGL and CGI-58 interactions at rest.

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