In vivo glucoregulation and tissue-specific glucose uptake in female Akt substrate 160 kDa knockout rats

Zheng, Xiaohua; Arias, Edward B.; Qi, Nathan; Saunders, Thomas L.; Cartee, Gregory D.

doi:10.1371/journal.pone.0223340

Cited by 11 publications

(6 citation statements)

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“…Muscle TBC1D1 abundance and pTBC1D1 Ser237 were unaltered by exercise or genotype. Consistent with earlier studies, 28,34,35 GLUT4 abundance of AS160-KO muscle was significantly lower than WT muscle, possibly due to lysosome-dependent GLUT4 degradation caused by AS160 deletion. 41 Rescuing muscle AS160 abundance in AS160-KO rats via AAV-WT-AS160 delivery eliminated the genotype difference in ISGU for both sedentary and exercised groups.…”

Section: Discussionsupporting

confidence: 91%

AS160 expression, but not AS160 Serine‐588, Threonine‐642, and Serine‐704 phosphorylation, is essential for elevated insulin‐stimulated glucose uptake by skeletal muscle from female rats after acute exercise

et al. 2023

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One exercise session can increase subsequent insulin‐stimulated glucose uptake (ISGU) by skeletal muscle in both sexes. We recently found that muscle expression and phosphorylation of key sites of Akt substrate of 160 kDa (AS160; also called TBC1D4) are essential for the full‐exercise effect on postexercise‐ISGU (PEX‐ISGU) in male rats. In striking contrast, AS160's role in increased PEX‐ISGU has not been rigorously tested in females. Our rationale was to address this major knowledge gap. Wild‐type (WT) and AS160‐knockout (KO) rats were either sedentary or acutely exercised. Adeno‐associated virus (AAV) vectors were engineered to express either WT‐AS160 or AS160 mutated on key serine and threonine residues (Ser588, Thr642, and Ser704) to alanine to prevent their phosphorylation. AAV vectors were delivered to the muscle of AS160‐KO rats to determine if WT‐AS160 or phosphorylation‐inactivated AS160 would influence PEX‐ISGU. AS160‐KO rats have lower skeletal muscle abundance of the GLUT4 glucose transporter protein. This GLUT4 deficit was rescued using AAV delivery of GLUT4 to determine if eliminating muscle GLUT4 deficiency would normalize PEX‐ISGU. The novel results were as follows: (1) AS160 expression was required for greater PEX‐ISGU; (2) rescuing muscle AS160 expression in AS160‐KO rats restored elevated PEX‐ISGU; (3) AS160's essential role for the postexercise increase in ISGU was not attributable to reduced muscle GLUT4 content; and (4) AS160 phosphorylation on Ser588, Thr642, and Ser704 was not essential for greater PEX‐ISGU. In conclusion, these novel findings revealed that three phosphosites widely proposed to influence PEX‐ISGU are not required for this important outcome in female rats.

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Section: Discussionsupporting

confidence: 91%

AS160 expression, but not AS160 Serine‐588, Threonine‐642, and Serine‐704 phosphorylation, is essential for elevated insulin‐stimulated glucose uptake by skeletal muscle from female rats after acute exercise

et al. 2023

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“…Despite the clinical relevance of AS160, contemporary mouse models have limitations in their utility to evaluate the metabolic influence of this protein. Knockin, knockout or knockdown of full or partial AS160 alters GLUT4 vesicle regulation, increasing GLUT4 membrane expression chronically, with no insulin responsiveness, and causing GLUT4 degradation [35,36,[66][67][68][69][70][71]. Since insulin-responsive changes in glucose uptake are critical for the metabolic flexibility and efficiency of myocytes, insight into the role of AS160 in this regulatory pathway cannot be effectively obtained in models where insulin sensitivity has been lost.…”

Section: Discussionmentioning

confidence: 99%

A peptide of the amino-terminus of GRK2 induces hypertrophy and yet elicits cardioprotection after pressure overload

Błędzka

Manaserh

Grondolsky

et al. 2021

Journal of Molecular and Cellular Cardiology

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G protein-coupled receptor (GPCR) kinase 2 (GRK2) expression and activity are elevated early on in response to several forms of cardiovascular stress and are a hallmark of heart failure. Interestingly, though, in addition to its well-characterized role in regulating GPCRs, mounting evidence suggests a GRK2 "interactome" that underlies a great diversity in its functional roles. Several such GRK2 interacting partners are important for adaptive and maladaptive myocyte growth; therefore, an understanding of domain-specific interactions with signaling and regulatory molecules could lead to novel targets for heart failure therapy. Herein, we subjected transgenic mice with cardiac restricted expression of a short, amino terminal fragment of GRK2 (βARKnt) to pressure overload and found that unlike their littermate controls or previous GRK2 fragments, they exhibited an increased left ventricular wall thickness and mass prior to cardiac stress that underwent proportional hypertrophic growth to controls after acute pressure overload. Importantly, despite this enlarged heart, βARKnt mice did not undergo the expected transition to heart failure observed in controls. Further, βARKnt expression limited adverse left ventricular remodeling and increased cell survival signaling. Proteomic analysis to identify βARKnt binding partners that may underlie the improved cardiovascular phenotype uncovered a selective functional interaction of both endogenous GRK2 and βARKnt with AKT substrate of 160 kDa (AS160). AS160 has emerged as a key downstream regulator of insulin signaling, integrating physiological and metabolic cues to couple energy demand to membrane recruitment of Glut4. Our preliminary data indicate that in βARKnt mice, cardiomyocyte insulin signaling is improved during stress, with a coordinate increase in spare respiratory activity and ATP production without metabolite switching. Surprisingly, these studies also revealed a significant decrease in gonadal fat weight, equivalent to human abdominal fat, in male βARKnt mice at baseline and following cardiac stress. These data suggest that the enhanced AS160-mediated signaling in the βARKnt mice may ameliorate pathological cardiac remodeling through direct modulation of insulin signaling within cardiomyocytes, and translate these to beneficial effects on systemic metabolism.

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“…WT wild type, D4KO Tbc1d4-knockout heart. Conversely, prior studies in TBC1D4-deficient female and male rats report increased cardiac 2-deoxyglucose uptake in vivo during a hyperinsulinemic-euglycemic clamp, despite of reduced abundance of GLUT4 and unchanged levels of glucose transporters GLUT1, GLUT8 and SGLT1 in the heart [29,30]. Further studies are needed to investigate the subcellular localization of cardiac GLUT4 in these animals.…”

Section: Discussionmentioning

confidence: 86%

Deletion of Tbc1d4/As160 abrogates cardiac glucose uptake and increases myocardial damage after ischemia/reperfusion

Binsch

Barbosa

Hansen-Dille

et al. 2023

Cardiovasc Diabetol

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Background Type 2 Diabetes mellitus (T2DM) is a major risk factor for cardiovascular disease and associated with poor outcome after myocardial infarction (MI). In T2DM, cardiac metabolic flexibility, i.e. the switch between carbohydrates and lipids as energy source, is disturbed. The RabGTPase-activating protein TBC1D4 represents a crucial regulator of insulin-stimulated glucose uptake in skeletal muscle by controlling glucose transporter GLUT4 translocation. A human loss-of-function mutation in TBC1D4 is associated with impaired glycemic control and elevated T2DM risk. The study’s aim was to investigate TBC1D4 function in cardiac substrate metabolism and adaptation to MI. Methods Cardiac glucose metabolism of male Tbc1d4-deficient (D4KO) and wild type (WT) mice was characterized using in vivo [18F]-FDG PET imaging after glucose injection and ex vivo basal/insulin-stimulated [3H]-2-deoxyglucose uptake in left ventricular (LV) papillary muscle. Mice were subjected to cardiac ischemia/reperfusion (I/R). Heart structure and function were analyzed until 3 weeks post-MI using echocardiography, morphometric and ultrastructural analysis of heart sections, complemented by whole heart transcriptome and protein measurements. Results Tbc1d4-knockout abolished insulin-stimulated glucose uptake in ex vivo LV papillary muscle and in vivo cardiac glucose uptake after glucose injection, accompanied by a marked reduction of GLUT4. Basal cardiac glucose uptake and GLUT1 abundance were not changed compared to WT controls. D4KO mice showed mild impairments in glycemia but normal cardiac function. However, after I/R D4KO mice showed progressively increased LV endsystolic volume and substantially increased infarction area compared to WT controls. Cardiac transcriptome analysis revealed upregulation of the unfolded protein response via ATF4/eIF2α in D4KO mice at baseline. Transmission electron microscopy revealed largely increased extracellular matrix (ECM) area, in line with decreased cardiac expression of matrix metalloproteinases of D4KO mice. Conclusions TBC1D4 is essential for insulin-stimulated cardiac glucose uptake and metabolic flexibility. Tbc1d4-deficiency results in elevated cardiac endoplasmic reticulum (ER)-stress response, increased deposition of ECM and aggravated cardiac damage following MI. Hence, impaired TBC1D4 signaling contributes to poor outcome after MI.

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In vivo glucoregulation and tissue-specific glucose uptake in female Akt substrate 160 kDa knockout rats

Cited by 11 publications

References 50 publications

AS160 expression, but not AS160 Serine‐588, Threonine‐642, and Serine‐704 phosphorylation, is essential for elevated insulin‐stimulated glucose uptake by skeletal muscle from female rats after acute exercise

AS160 expression, but not AS160 Serine‐588, Threonine‐642, and Serine‐704 phosphorylation, is essential for elevated insulin‐stimulated glucose uptake by skeletal muscle from female rats after acute exercise

A peptide of the amino-terminus of GRK2 induces hypertrophy and yet elicits cardioprotection after pressure overload

Deletion of Tbc1d4/As160 abrogates cardiac glucose uptake and increases myocardial damage after ischemia/reperfusion

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