Contraction regulates site-specific phosphorylation of TBC1D1 in skeletal muscle

Vichaiwong, Kanokwan; Purohit, Suneet; Ding, An; Toyoda, Tarō; Jessen, Niels; Hirshman, Michael F.; Goodyear, Laurie J.

doi:10.1042/bj20101100

Cited by 91 publications

(129 citation statements)

References 45 publications

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“…On the other hand, mutation of Ser-237 to alanine has no effect on the APPL2-TBC1D1 interaction as well as on the suppressive effect of TBC1D1 on insulin-stimulated glucose uptake. Of note, Ser-237 is phosphorylated by AMPK in response to contraction but not by insulin stimulation (40)(41)(42), suggesting that APPL2 may only regulate glucose uptake through the TBC1D1 signaling pathway in response to insulin and not contraction in skeletal muscle.…”

Section: Discussionmentioning

confidence: 99%

The Adaptor Protein APPL2 Inhibits Insulin-Stimulated Glucose Uptake by Interacting With TBC1D1 in Skeletal Muscle

et al. 2014

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Insulin stimulates glucose uptake by promoting the trafficking of GLUT4 to the plasma membrane in muscle cells, and impairment of this insulin action contributes to hyperglycemia in type 2 diabetes. The adaptor protein APPL1 potentiates insulin-stimulated Akt activation and downstream actions. However, the physiological functions of APPL2, a close homolog of APPL1, in regulating glucose metabolism remain elusive. We show that insulin-evoked plasma membrane recruitment of GLUT4 and glucose uptake are impaired by APPL2 overexpression but enhanced by APPL2 knockdown. Likewise, conditional deletion of APPL2 in skeletal muscles enhances insulin sensitivity, leading to an improvement in glucose tolerance. We identified the Rab-GTPaseactivating protein TBC1D1 as an interacting partner of APPL2. Insulin stimulates TBC1D1 phosphorylation on serine 235, leading to enhanced interaction with the BAR domain of APPL2, which in turn suppresses insulinevoked TBC1D1 phosphorylation on threonine 596 in cultured myotubes and skeletal muscle. Substitution of serine 235 with alanine diminishes APPL2-mediated inhibition on insulin-dependent TBC1D1 phosphorylation on threonine 596 and the suppressive effects of TBC1D1 on insulin-induced glucose uptake and GLUT4 translocation to the plasma membrane in cultured myotubes. Therefore, the APPL2-TBC1D1 interaction is a key step to fine tune insulin-stimulated glucose uptake by regulating the membrane recruitment of GLUT4 in skeletal muscle.

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Section: Discussionmentioning

confidence: 99%

The Adaptor Protein APPL2 Inhibits Insulin-Stimulated Glucose Uptake by Interacting With TBC1D1 in Skeletal Muscle

et al. 2014

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“…These results are in line with recent studies in healthy lean (24,25) and obese (26) subjects. Mutational studies in mice have shown that lack of phosphorylation on multiple sites on TBC1D1, including Ser 237 and Thr 596 , reduce contraction-stimulated glucose uptake in skeletal muscle (27,45). Furthermore, the TBC1D1 conventional knockout mouse model shows impaired muscle glucose uptake in response to exercise (46).…”

Section: Discussionmentioning

confidence: 99%

Intact Regulation of the AMPK Signaling Network in Response to Exercise and Insulin in Skeletal Muscle of Male Patients With Type 2 Diabetes: Illumination of AMPK Activation in Recovery From Exercise

et al. 2016

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Current evidence on exercise-mediated AMPK regulation in skeletal muscle of patients with type 2 diabetes (T2D) is inconclusive. This may relate to inadequate segregation of trimeric complexes in the investigation of AMPK activity. We examined the regulation of AMPK and downstream targets ACC-b, TBC1D1, and TBC1D4 in muscle biopsy specimens obtained from 13 overweight/obese patients with T2D and 14 weight-matched male control subjects before, immediately after, and 3 h after exercise. ences in these responses were observed between patients with T2D and control subjects. Subjects were also studied by euglycemic-hyperinsulinemic clamps performed at rest and 3 h after exercise. We found no evidence for insulin to regulate AMPK activity. Thus, AMPK signaling is not compromised in muscle of patients with T2D during exercise and insulin stimulation. Our results reveal a hitherto unrecognized activation of specific AMPK complexes in exercise recovery. We hypothesize that the differential regulation of AMPK complexes plays an important role for muscle metabolism and adaptations to exercise.

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“…TBC1D1 is a closely related paralog of TBC1D4 that is regulated by both AMPK and Akt, and regulates glucose transport (37)(38)(39)(40). As AMPK increases the phosphorylation of TBC1D1 Ser 231 in response to contraction and AICAR, and as Akt increases the phosphorylation of Thr 590 in response to insulin, we investigated whether changes in TBC1D1 phosphorylation occurred in parallel with the increase in muscle insulin sensitivity after prior AICAR stimulation.…”

Section: Tbc1d1 Signalingmentioning

confidence: 99%

Prior AICAR Stimulation Increases Insulin Sensitivity in Mouse Skeletal Muscle in an AMPK-Dependent Manner

et al. 2014

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An acute bout of exercise increases glucose uptake in skeletal muscle by an insulin-independent mechanism. In the period after exercise, insulin sensitivity to increased glucose uptake is enhanced. The molecular mechanisms underpinning this phenomenon are poorly understood but appear to involve an increased cell surface abundance of GLUT4. While increased proximal insulin signaling does not seem to mediate this effect, elevated phosphorylation of TBC1D4, a downstream target of both insulin (Akt) and exercise (AMPK) signaling, appears to play a role. The main purpose of this study was to determine whether AMPK activation increases skeletal muscle insulin sensitivity. We found that prior AICAR stimulation of wild-type mouse muscle increases insulin sensitivity to stimulate glucose uptake. However, this was not observed in mice with reduced or ablated AMPK activity in skeletal muscle. Furthermore, prior AICAR stimulation enhanced insulin-stimulated phosphorylation of TBC1D4 at Thr 649 and Ser 711 in wild-type muscle only. These phosphorylation events were positively correlated with glucose uptake. Our results provide evidence to support that AMPK activation is sufficient to increase skeletal muscle insulin sensitivity. Moreover, TBC1D4 phosphorylation may facilitate the effect of prior AMPK activation to enhance glucose uptake in response to insulin.The effect of insulin on skeletal muscle glucose uptake is increased in the period after a single bout of exercise. This phenomenon is observed in muscle from both humans and rodents (1-6) and may persist for up to 48 h after exercise, depending on carbohydrate availability (7-9). Improved muscle insulin sensitivity postexercise is mediated by one or several local contraction-induced mechanisms (10) involving both enhanced transport and intracellular processing of glucose. This period is characterized by increased GLUT4 protein abundance at the plasma membrane and enhanced glycogen synthase activity (11,12). These changes occur independent of global protein synthesis (13), including both total GLUT4 and glycogen synthase protein content (4,11), and are independent of changes in proximal insulin signaling, including Akt activation (3,4,(13)(14)(15)(16)(17).AMPK is a heterotrimeric complex consisting of catalytic (a1/a2) and regulatory subunits (b1/b2 and g1/g2/g3). Of the 12 heterotrimeric combinations, only 3 and 5 combinations have been found in the skeletal muscle of human and mouse, respectively (18,19). AMPK is activated in response to various stimuli that increase cellular energy stress (e.g., metformin, hypoxia, hyperosmolarity, muscle contraction, and exercise) (20). With energy stress, intracellular concentrations of AMP and ADP accumulate. This activates AMPK allosterically and decreases the ability of upstream phosphatases to dephosphorylate Thr 172 , which further increases AMPK phosphorylation and activity (21). Like exercise, AICAR increases AMPK activity in skeletal muscle (22), which partly mimics the metabolic changes observed during muscle contraction (...

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Contraction regulates site-specific phosphorylation of TBC1D1 in skeletal muscle

Cited by 91 publications

References 45 publications

The Adaptor Protein APPL2 Inhibits Insulin-Stimulated Glucose Uptake by Interacting With TBC1D1 in Skeletal Muscle

The Adaptor Protein APPL2 Inhibits Insulin-Stimulated Glucose Uptake by Interacting With TBC1D1 in Skeletal Muscle

Intact Regulation of the AMPK Signaling Network in Response to Exercise and Insulin in Skeletal Muscle of Male Patients With Type 2 Diabetes: Illumination of AMPK Activation in Recovery From Exercise

Prior AICAR Stimulation Increases Insulin Sensitivity in Mouse Skeletal Muscle in an AMPK-Dependent Manner

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