Growth hormone and Insulin-like growth factor-I (IGF-I) modulate the expression of L-type amino acid transporters in the muscles of spontaneous dwarf rats and L6 and C2C12 myocytes

Sawa, Ran; Nishida, Hikaru; Yamamoto, Yu; Wake, Ikumi; Kai, Noriko; Kikkawa, Ushio; Okimura, Yasuhiko

doi:10.1016/j.ghir.2018.09.002

Cited by 10 publications

(6 citation statements)

References 22 publications

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“…BCAA supplements, including valine, leucine, and isoleucine, have been proposed to alleviate exercise-induced fatigue 15,44 and inhibit muscle atrophy. 137 The administration of BCAA improved running performance by decreasing extracellular tryptophan, 15 suggesting that BCAA inhibit intracerebral tryptophan release and uptake from the circulation. Moreover, rats on BCAA-supplemented diets showed a decreased kynurenic acid level in the brain.…”

Section: Alleviating the Effect Of Fatigue Using Supplementsmentioning

confidence: 99%

Potential Role of Neuroactive Tryptophan Metabolites in Central Fatigue: Establishment of the Fatigue Circuit

Yamashita

2020

Int J�Tryptophan�Res

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Central fatigue leads to reduced ability to perform mental tasks, disrupted social life, and impaired brain functions from childhood to old age. Regarding the neurochemical mechanism, neuroactive tryptophan metabolites are thought to play key roles in central fatigue. Previous studies have supported the “tryptophan-serotonin enhancement hypothesis” in which tryptophan uptake into extensive brain regions enhances serotonin production in the rat model of exercise-induced fatigue. However, serotonin was transiently released after 30 minutes of treadmill running to exhaustion, but this did not reflect the duration of fatigue. In addition, as the vast majority of tryptophan is metabolized along the kynurenine pathway, possible involvement of the tryptophan-kynurenine pathway in the mechanism of central fatigue induction has been pointed out. More recently, our study demonstrated that uptake of tryptophan and kynurenine derived from the peripheral circulation into the brain enhances kynurenic acid production in rat brain in sleep deprivation–induced central fatigue, but without change in serotonin activity. In particular, dynamic change in glial-neuronal interactive processes within the hypothalamus-hippocampal circuit causes central fatigue. Furthermore, increased tryptophan-kynurenine pathway activity in this circuit causes reduced memory function. This indicates a major potential role for the endogenous tryptophan-kynurenine pathway in central fatigue, which supports the “tryptophan-kynurenine enhancement hypothesis.” Here, we review research on the basic neuronal mechanism underlying central fatigue induced by neuroactive tryptophan metabolites. Notably, these basic findings could contribute to our understanding of latent mental problems associated with central fatigue.

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Section: Alleviating the Effect Of Fatigue Using Supplementsmentioning

confidence: 99%

Potential Role of Neuroactive Tryptophan Metabolites in Central Fatigue: Establishment of the Fatigue Circuit

Yamashita

2020

Int J�Tryptophan�Res

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“…Also, our present results confirmed pronounced effects on cell proliferation by IGF-1 knockdown (Fig 2B). An extended hypothesis may be that amino acid availability regulates muscle IGF-1 production to participate in processes associated with amino acid transport [31]. Such observations are reported in other cell types, as brain cells, where inhibition of IGF-1R caused a significant decrease in glutamate transporters on cell surface [32].…”

Section: Discussionmentioning

confidence: 86%

Initiation of muscle protein synthesis was unrelated to simultaneously upregulated local production of IGF-1 by amino acids in non-proliferating L6 muscle cells

2022

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Background IGF-1 is considered an important regulator of muscle protein synthesis. However, its role in stimulation of muscle protein synthesis by amino acids (AA) is not clear, despite pronounced alterations in IGF-1 mRNA expression and signaling in muscle tissues by feeding. This study evaluates the role of locally produced IGF-1 and IGF-1 signaling when skeletal muscle protein synthesis is activated by increased amino acid availability in confluent, non-proliferating cells. Methods L6 skeletal muscle cells were subjected to amino acid starvation (24 h, 0.14 mM) followed by 18 h amino acid refeeding in Low AA (0.28 mM) or High AA concentrations (9 mM). Protein synthesis rates were estimated by L-[U-14C]-phenylalanine incorporation into cellular proteins. IGF-1 and IGF-1 receptor mRNA expression were quantified by real time PCR. SiRNA knockdown, antibodies and chemical inhibitors were used to attenuate muscle IGF-1 production and signaling. Results High AA concentrations (9mM) increased IGF-1 mRNA expression (+ 30%, p<0.05) and increased L-[U-14C]-phenylalanine incorporation compared to Low AA in confluent, non-proliferating muscle cells. Blocking IGF-1 signaling by chemical inhibitors reduced IGF-1 mRNA upregulation (~50%, p< 0.01), without decrease of protein synthesis. SiRNA knockdown of IGF-1 reduced protein synthesis, mainly explained by reduced cell proliferation. High AA or IGF-1 inhibitors did not change IGF-1 receptor mRNA expressions. Conclusion Amino acids increased IGF-1 mRNA expression and stimulated muscle protein synthesis. However, simultaneous upregulation of IGF-1 mRNA did not relate to increased protein synthesis by amino acids. The results indicate that increased IGF-1 mRNA expression is rather a covariate to amino acid initiation of protein synthesis in non-proliferating muscle cells; effects that may be related to unrecognized metabolic activities, such as transport of amino acids.

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“…17,19 In terms of the amino acid metabolism, it is interesting that one of GH appears to modulate the mTOR pathway partially through the stimulated expression of L-type amino acid transporters that delivered BCAAs. 42 Although this relationship has garnered little attention in AT, the potential importance between GH function and BCAA metabolism warrants further exploration. to have more pronounced alterations in immune cell infiltration 38 and fibrosis, 24 promoting a 'pro-inflammatory' state in that depot.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, both GH and BCAAs modulate the mTOR pathway and have been linked to obesity, T2DM, as well as neuropathologies such as Alzheimer's disease 41 . At least in muscle, GH appears to modulate the mTOR pathway partially through the stimulated expression of L‐type amino acid transporters that delivered BCAAs 42 . Although this relationship has garnered little attention in AT, the potential importance between GH function and BCAA metabolism warrants further exploration.…”

Section: Discussionmentioning

confidence: 99%

Differential gene signature in adipose tissue depots of growth hormone transgenic mice

Duran‐Ortiz

Young

Jara

et al. 2020

J Neuroendocrinology

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Bovine growth hormone (bGH) transgenic mice mimic the clinical condition of acromegaly, having high circulating growth hormone (GH) levels. These mice are giant, have decreased adipose tissue (AT) mass, impaired glucose metabolism and a shortened lifespan. The detrimental effects of excess GH have been suggested, in part, to be a result of its depot-specific actions on AT. To investigate this relationship, we evaluated gene expression, biological mechanisms, cellular pathways and predicted microRNA (miRNA) in two AT depots (subcutaneous [Subq] and epididymal [Epi]) from bGH and littermate controls using RNA sequencing analysis. Two analyses on the differentially expressed genes (DEG) were performed: (i) comparison of the same AT depot between bGH and wild-type (WT) mice (genotype comparison) and (ii) comparison of Subq and Epi AT depots within the same genotype (depot comparison). For the genotype comparison, we found a higher number of significant DEG in the Subq AT depot of bGH mice compared to WT controls, corroborating previous reports that GH has a greater impact on the Subq depot. Furthermore, most of the DEG in bGH mice were not shared by WT mice, suggesting that excess GH induces the expression of genes not commonly present in AT. Through gene ontology and pathway analysis, the genotype comparison revealed that the DEG of the Subq depot of bGH mice relate to fatty acid oxidation, branched-chain amino acid degradation and the immune system. Additionally, the AT depot comparison showed that the immune cell activation and T-cell response appear up-regulated in the Subq compared to the Epi AT depot. The miRNA prediction also suggested a modulation of T-cell-related biological process in Subq. In summary, the present study provides a unique resource for understanding the specific differences in gene expression that are driven by both excess GH action and AT depot location.

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Growth hormone and Insulin-like growth factor-I (IGF-I) modulate the expression of L-type amino acid transporters in the muscles of spontaneous dwarf rats and L6 and C2C12 myocytes

Cited by 10 publications

References 22 publications

Potential Role of Neuroactive Tryptophan Metabolites in Central Fatigue: Establishment of the Fatigue Circuit

Potential Role of Neuroactive Tryptophan Metabolites in Central Fatigue: Establishment of the Fatigue Circuit

Initiation of muscle protein synthesis was unrelated to simultaneously upregulated local production of IGF-1 by amino acids in non-proliferating L6 muscle cells

Differential gene signature in adipose tissue depots of growth hormone transgenic mice

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