Adrenoceptor regulation of the mechanistic target of rapamycin in muscle and adipose tissue

Chia, Ling Yeong; Evans, Bronwyn A; Mukaida, Saori; Bengtsson, Tore; Hutchinson, Dana S.; Sato, Masaaki

doi:10.1111/bph.14616

Cited by 8 publications

(4 citation statements)

References 160 publications

(224 reference statements)

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“…Binding of ␤2 agonists to the receptor activates adenylate cyclase with generation of cyclic AMP and activation of protein kinase A (PKA). Chronic treatment with ␤2 agonists as clenbuterol leads to muscle hypertrophy through still poorly defined pathways, which appear to involve the IGF1-PI3K-Akt-mTOR cascade [18,19]. The role of PKA-dependent phosphorylation of the transcription factor CREB (cAMP response element binding protein) and associated coactivators in mediating muscle hypertrophy is not known, although the pro-hypertrophic factor MEF2 (see below) could be involved, as a dominant-negative CREB in postnatal mouse muscles caused muscle wasting that was associated with reduced expression of MEF2 target genes [see 20].…”

Section: β2-agonistsmentioning

confidence: 99%

Molecular Mechanisms of Skeletal Muscle Hypertrophy

Schiaffino

Reggiani

Akimoto

et al. 2021

JND

101

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Skeletal muscle hypertrophy can be induced by hormones and growth factors acting directly as positive regulators of muscle growth or indirectly by neutralizing negative regulators, and by mechanical signals mediating the effect of resistance exercise. Muscle growth during hypertrophy is controlled at the translational level, through the stimulation of protein synthesis, and at the transcriptional level, through the activation of ribosomal RNAs and muscle-specific genes. mTORC1 has a central role in the regulation of both protein synthesis and ribosomal biogenesis. Several transcription factors and co-activators, including MEF2, SRF, PGC-1α4, and YAP promote the growth of the myofibers. Satellite cell proliferation and fusion is involved in some but not all muscle hypertrophy models.

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Section: β2-agonistsmentioning

confidence: 99%

Molecular Mechanisms of Skeletal Muscle Hypertrophy

Schiaffino

Reggiani

Akimoto

et al. 2021

JND

101

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“…Activation of β‐ARs play an important role in the regulation of cardiovascular function, including positive inotropic and chronotropic effects. When β‐ARs are stimulated, typically by epinephrine or norepinephrine, the canonical Gαs‐adenylate cyclase (AC)‐cyclic AMP (cAMP)‐protein kinase A (PKA) signaling cascade is activated and further induces downstream signaling pathways (Chia et al., 2019 ). PKA activation due to loss of PKA the regulatory subunit 1α has been found to increase cardiomyocyte necrosis (Liu et al., 2021 ).There is an emerging role of cyclic nucleotides and cyclic nucleotide‐dependent protein kinases on the regulation of mTOR signaling (Shi & Collins, 2023 ), particularly the important role of cAMP/PKA in mTOR activation.…”

Section: Discussionmentioning

confidence: 99%

mTORC1 hyperactivation and resultant suppression of macroautophagy contribute to the induction of cardiomyocyte necroptosis by catecholamine surges

Cai,

Wu,

et al. 2024

Physiological Reports

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Previous studies revealed a controversial role of mechanistic target of rapamycin complex 1 (mTORC1) and mTORC1‐regulated macroautophagy in isoproterenol (ISO)‐induced cardiac injury. Here we investigated the role of mTORC1 and potential underlying mechanisms in ISO‐induced cardiomyocyte necrosis. Two consecutive daily injections of ISO (85 mg/kg, s.c.) or vehicle control (CTL) were administered to C57BL/6J mice with or without rapamycin (RAP, 5 mg/kg, i.p.) pretreatment. Western blot analyses showed that myocardial mTORC1 signaling and the RIPK1–RIPK3–MLKL necroptotic pathway were activated, mRNA expression analyses revealed downregulation of representative TFEB target genes, and Evan's blue dye uptake assays detected increased cardiomyocyte necrosis in ISO‐treated mice. However, RAP pretreatment prevented or significantly attenuated the ISO‐induced cardiomyocyte necrosis, myocardial inflammation, downregulation of TFEB target genes, and activation of the RIPK1–RIPK3–MLKL pathway. LC3‐II flux assays confirmed the impairment of myocardial autophagic flux in the ISO‐treated mice. In cultured neonatal rat cardiomyocytes, mTORC1 signaling was also activated by ISO, and inhibition of mTORC1 by RAP attenuated ISO‐induced cytotoxicity. These findings suggest that mTORC1 hyperactivation and resultant suppression of macroautophagy play a major role in the induction of cardiomyocyte necroptosis by catecholamine surges, identifying mTORC1 inhibition as a potential strategy to treat heart diseases with catecholamine surges.

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“…To our disappointment, Rapa only resulted in minimal improvement of morphological whitening. We speculated that its positive effects on autophagy flux were offset by its disturbance of multiple pathways, including protein synthesis and mitochondrial biogenesis [36,61]. Previous studies showed that mTORC1 is essential for BAT adaptation to cold and β-adrenergic stimulation through promoting mitochondrial biogenesis [62,63].…”

Section: Discussionmentioning

confidence: 99%

Postnatal Dexamethasone Therapy Impairs Brown Adipose Tissue Thermogenesis and Autophagy Flux in Neonatal Rat Pups

Chang¹,

Hou²,

Yu³

et al. 2022

Theranostics

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Rationale: Very preterm infants may require dexamethasone (Dex) for facilitating extubation or treating bronchopulmonary dysplasia. However, Dex may result in disturbance of metabolisms. This study was to investigate the effects of postnatal short course Dex exposure on brown adipose tissue (BAT) in neonatal rats. Method: Neonatal rats received either three consecutive doses of daily Dex (0.2 mg/kg/day) or saline from postnatal P1 to P3. We investigated the effects of Dex on BAT including thermogenesis, mitochondrial dynamics and autophagy flux. We also compared diurnal temperature variation between preterm infants who received systemic corticosteroid and their treatment-naïve controls. Results: Postnatal Dex treatment induced growth retardation, BAT whitening, UCP1 downregulation and cold intolerance in neonatal rats. BAT mitochondria were damaged, evident by loss of normal number, structure, and alignment of cristae. Mitochondrial fission-fusion balance was disrupted and skewed toward increased fusion, reflected by increased OPA1 and MFN2 and decreased DRP1, FIS1 and phosphorylated MFF protein levels. Autophagosome synthesis was increased but clearance was inhibited, indicated by accumulation of p62 protein after Dex treatment and no further increase of LC3-II after chloroquine co-treatment. While autophagy modulators, including chloroquine and rapamycin, did not improve UCP1 downregulation and BAT whitening, AMPK activators could partially rescue these damages. We also demonstrated that preterm infants had higher diurnal temperature variation during corticosteroid treatment. Conclusions: Postnatal short course Dex impaired BAT mitochondrial function and autophagy flux in rat pups. AMPK activators had the potential to rescue the damage.

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Adrenoceptor regulation of the mechanistic target of rapamycin in muscle and adipose tissue

Cited by 8 publications

References 160 publications

Molecular Mechanisms of Skeletal Muscle Hypertrophy

Molecular Mechanisms of Skeletal Muscle Hypertrophy

mTORC1 hyperactivation and resultant suppression of macroautophagy contribute to the induction of cardiomyocyte necroptosis by catecholamine surges

Postnatal Dexamethasone Therapy Impairs Brown Adipose Tissue Thermogenesis and Autophagy Flux in Neonatal Rat Pups

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