CL316,243, a selective β3-adrenoceptor agonist, activates protein translation through mTOR/p70S6K signaling pathway in rat skeletal muscle cells

Miniaci, Maria Concetta; Bucci, Mariarosaria; Santamaria, Rita; Irace, Carlo; Cantalupo, Anna; Cirino, Giuseppe; Scotto, P.

doi:10.1007/s00424-012-1213-9

Cited by 8 publications

(10 citation statements)

References 54 publications

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“…Indeed, the CL316,243-induced increase of p70 S6K was markedly inhibited by wortmannin, a PI3K inhibitor, and rapamycin, a specific inhibitor of mTOR12. Based on these observations, we examined whether the in vivo administration of CL316,243 modulates the expression of p70 S6K and its downstream target, rpS6, in skeletal muscles obtained from mice treated with CL316,243 or vehicle.…”

Section: Resultsmentioning

confidence: 99%

“…Most of these factors control the rate of protein turnover at the level of transcription, translation, degradation or a combination of these29. According to our previous studies in vitro , β3-ARs stimulation up-regulates protein synthesis and this effect is likely due to the activation of components of the translational machinery, including the ribosomal protein S612. Here, the use of an in vivo model confirmed our previous in vitro data, thus providing a further demonstration that CL316,243 has the potential to regulate protein metabolism in skeletal muscle by increasing the expression of mTOR targets in the long term.…”

Section: Discussionmentioning

confidence: 96%

“…Even though metabolic effects of β3-AR activation are highly recognized, less is known about the impact of β3-ARs in the regulation of skeletal muscle structure and function. Using a β3-AR selective agonist, CL316,243, we have recently demonstrated in vitro that β3-ARs play a critical role in the regulation of protein metabolism in skeletal muscle12. In particular, we found that CL316,243 induced a significant increase of skeletal muscle constitutive proteins into muscle cell proteins such as myosin heavy chain, myosin light chain, and actin in rat L6 myocytes.…”

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confidence: 82%

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CL316,243, a β3-adrenergic receptor agonist, induces muscle hypertrophy and increased strength

Puzzo

Raiteri

Castaldo

et al. 2016

Sci Rep

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Studies in vitro have demonstrated that β3-adrenergic receptors (β3-ARs) regulate protein metabolism in skeletal muscle by promoting protein synthesis and inhibiting protein degradation. In this study, we evaluated whether activation of β3-ARs by the selective agonist CL316,243 modifies the functional and structural properties of skeletal muscles of healthy mice. Daily injections of CL316,243 for 15 days resulted in a significant improvement in muscle force production, assessed by grip strength and weight tests, and an increased myofiber cross-sectional area, indicative of muscle hypertrophy. In addition, atomic force microscopy revealed a significant effect of CL316,243 on the transversal stiffness of isolated muscle fibers. Interestingly, the expression level of mammalian target of rapamycin (mTOR) downstream targets and neuronal nitric oxide synthase (NOS) was also found to be enhanced in tibialis anterior and soleus muscles of CL316,243 treated mice, in accordance with previous data linking β3-ARs to mTOR and NOS signaling pathways. In conclusion, our data suggest that CL316,243 systemic administration might be a novel therapeutic strategy worthy of further investigations in conditions of muscle wasting and weakness associated with aging and muscular diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 82%

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CL316,243, a β3-adrenergic receptor agonist, induces muscle hypertrophy and increased strength

Puzzo

Raiteri

Castaldo

et al. 2016

Sci Rep

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“…The remaining IUGR lambs were randomly assigned to also receive either no postnatal intervention (IUGR; n = 14) or to receive daily oral ADRβ modifiers (IUGR-AR, n = 8). This daily treatment consisted of 20 µg kg −1 day −1 clenbuterol (ADRβ2 agonist), 400 µg kg −1 day −1 atenolol (ADRβ1 antagonist) and 2 µg kg −1 day −1 SR59230A J Physiol 597.24 (ADRβ3 antagonist), given orally in 50 ml of milk replacer (Coleman et al 1988;MacRae et al 1988;Manara et al 1996;Torneke et al 1998;Chiou et al 2000;Despres et al 2002;Kanzler et al 2011;Miniaci et al 2013). The doses of clenbuterol, atenolol and SR59230A were chosen to provide the lowest effective dose in order to minimize potential off-target effects.…”

Section: Ethical Approvalmentioning

confidence: 99%

Postnatal β2 adrenergic treatment improves insulin sensitivity in lambs with IUGR but not persistent defects in pancreatic islets or skeletal muscle

Yates

Camacho

Kelly

et al. 2019

The Journal of Physiology

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Key points Previous studies in fetuses with intrauterine growth restriction (IUGR) have shown that adrenergic dysregulation was associated with low insulin concentrations and greater insulin sensitivity. Although whole‐body glucose clearance is normal, 1‐month‐old lambs with IUGR at birth have higher rates of hindlimb glucose uptake, which may compensate for myocyte deficiencies in glucose oxidation. Impaired glucose‐stimulated insulin secretion in IUGR lambs is due to lower intra‐islet insulin availability and not from glucose sensing. We investigated adrenergic receptor (ADR) β2 desensitization by administering oral ADRβ modifiers for the first month after birth to activate ADRβ2 and antagonize ADRβ1/3. In IUGR lambs ADRβ2 activation increased whole‐body glucose utilization rates and insulin sensitivity but had no effect on isolated islet or myocyte deficiencies. IUGR establishes risk for developing diabetes. In IUGR lambs we identified disparities in key aspects of glucose‐stimulated insulin secretion and insulin‐stimulated glucose oxidation, providing new insights into potential mechanisms for this risk. Abstract Placental insufficiency causes intrauterine growth restriction (IUGR) and disturbances in glucose homeostasis with associated β adrenergic receptor (ADRβ) desensitization. Our objectives were to measure insulin‐sensitive glucose metabolism in neonatal lambs with IUGR and to determine whether daily treatment with ADRβ2 agonist and ADRβ1/β3 antagonists for 1 month normalizes their glucose metabolism. Growth, glucose‐stimulated insulin secretion (GSIS) and glucose utilization rates (GURs) were measured in control lambs, IUGR lambs and IUGR lambs treated with adrenergic receptor modifiers: clenbuterol atenolol and SR59230A (IUGR‐AR). In IUGR lambs, islet insulin content and GSIS were less than in controls; however, insulin sensitivity and whole‐body GUR were not different from controls. Of importance, ADRβ2 stimulation with β1/β3 inhibition increases both insulin sensitivity and whole‐body glucose utilization in IUGR lambs. In IUGR and IUGR‐AR lambs, hindlimb GURs were greater but fractional glucose oxidation rates and ex vivo skeletal muscle glucose oxidation rates were lower than controls. Glucose transporter 4 (GLUT4) was lower in IUGR and IUGR‐AR skeletal muscle than in controls but GLUT1 was greater in IUGR‐AR. ADRβ2, insulin receptor, glycogen content and citrate synthase activity were similar among groups. In IUGR and IUGR‐AR lambs heart rates were greater, which was independent of cardiac ADRβ1 activation. We conclude that targeted ADRβ2 stimulation improved whole‐body insulin sensitivity but minimally affected defects in GSIS and skeletal muscle glucose oxidation. We show that risk factors for developing diabetes are independent of postnatal catch‐up growth in IUGR lambs as early as 1 month of age and are inherent to the islets and myocytes.

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“…We have previously shown in skeletal muscles that β3-adrenergic receptor signaling recruits phosphatidylinositol 3-kinase (PI3K) pathway via Gi/o protein (Miniaci et al, 2013;Puzzo et al, 2016).…”

Section: Pi3k Is Necessary For Cl-induced Depression Of Pf-pc Synapmentioning

confidence: 99%

Role of β3‐adrenergic receptor in the modulation of synaptic transmission and plasticity in mouse cerebellar cortex

Lippiello

Hoxha

Cristiano

et al. 2020

J of Neuroscience Research

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CL316,243, a selective β3-adrenoceptor agonist, activates protein translation through mTOR/p70S6K signaling pathway in rat skeletal muscle cells

Cited by 8 publications

References 54 publications

CL316,243, a β3-adrenergic receptor agonist, induces muscle hypertrophy and increased strength

CL316,243, a β3-adrenergic receptor agonist, induces muscle hypertrophy and increased strength

Postnatal β2 adrenergic treatment improves insulin sensitivity in lambs with IUGR but not persistent defects in pancreatic islets or skeletal muscle

Role of β3‐adrenergic receptor in the modulation of synaptic transmission and plasticity in mouse cerebellar cortex

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