Low Levels of Serum Tryptophan Underlie Skeletal Muscle Atrophy

Ninomiya, Soranobu; Nakamura, Nobuhiko; Nakamura, Hiroshi; Mizutani, Taku; Kaneda, Y.; Yamaguchi, Kimihiro; Matsumoto, Tomohiro; Kitagawa, Junichi; Kanemura, Nobuhiro; Shiraki, Makoto; Hara, Takeshi; Shimizu, Masahito; Tsurumi, Hisashi

doi:10.3390/nu12040978

Cited by 26 publications

(29 citation statements)

References 37 publications

(48 reference statements)

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“…These findings are in agreement with previously reported role of TNFα in the utilization of glucose, formation of lactate [ 48 ] and nitrogen metabolism [ 49 ]. Notably, in the serum of elderly people affected by age-associated skeletal muscle atrophy, low levels of tryptophan and increased proline concentrations have been reported [ 50 , 51 ]. TNFα plays a crucial role in the metabolic alteration that occurs in cancer cachexia [ 52 ], causing an increase in expenditure of energy, altered lipid and carbohydrate metabolism and insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

Role of Sphingosine 1-Phosphate Signalling Axis in Muscle Atrophy Induced by TNFα in C2C12 Myotubes

Bernacchioni

Ghini

Squecco

et al. 2021

IJMS

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Skeletal muscle atrophy is characterized by a decrease in muscle mass causing reduced agility, increased fatigability and higher risk of bone fractures. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNFα), are strong inducers of skeletal muscle atrophy. The bioactive sphingolipid sphingosine 1-phoshate (S1P) plays an important role in skeletal muscle biology. S1P, generated by the phosphorylation of sphingosine catalyzed by sphingosine kinase (SK1/2), exerts most of its actions through its specific receptors, S1P1–5. Here, we provide experimental evidence that TNFα induces atrophy and autophagy in skeletal muscle C2C12 myotubes, modulating the expression of specific markers and both active and passive membrane electrophysiological properties. NMR-metabolomics provided a clear picture of the deep remodelling of skeletal muscle fibre metabolism induced by TNFα challenge. The cytokine is responsible for the modulation of S1P signalling axis, upregulating mRNA levels of S1P2 and S1P3 and downregulating those of SK2. TNFα increases the phosphorylated form of SK1, readout of its activation. Interestingly, pharmacological inhibition of SK1 and specific antagonism of S1P3 prevented the increase in autophagy markers and the changes in the electrophysiological properties of C2C12 myotubes without affecting metabolic remodelling induced by the cytokine, highlighting the involvement of S1P signalling axis on TNFα-induced atrophy in skeletal muscle.

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Section: Discussionmentioning

confidence: 99%

Role of Sphingosine 1-Phosphate Signalling Axis in Muscle Atrophy Induced by TNFα in C2C12 Myotubes

Bernacchioni

Ghini

Squecco

et al. 2021

IJMS

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“…Importantly, Trp and its metabolites, including kynurenine, are closely associated with age-related diseases and lifespan [133]. Additionally, Ninomiya et al recently reported that serum concentration of Trp is positively correlated with the volume of skeletal muscles in patients with diffuse large B-cell lymphoma [134]. They also showed that fibre diameters in the tibialis anterior of C57BL/6 mice fed with a Trp-deficient diet were smaller than those in mice fed with a standard diet, suggesting a critical role of Trp in regulating muscle mass.…”

Section: The Multiple Actions Of Ace2 Outside Of the Rasmentioning

confidence: 99%

ACE2, angiotensin 1-7 and skeletal muscle: review in the era of COVID-19

2020

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Angiotensin converting enzyme-2 (ACE2) is a multifunctional transmembrane protein recently recognised as the entry receptor of the virus causing COVID-19. In the renin–angiotensin system (RAS), ACE2 cleaves angiotensin II (Ang II) into angiotensin 1-7 (Ang 1-7), which is considered to exert cellular responses to counteract the activation of the RAS primarily through a receptor, Mas, in multiple organs including skeletal muscle. Previous studies have provided abundant evidence suggesting that Ang 1-7 modulates multiple signalling pathways leading to protection from pathological muscle remodelling and muscle insulin resistance. In contrast, there is relatively little evidence to support the protective role of ACE2 in skeletal muscle. The potential contribution of endogenous ACE2 to the regulation of Ang 1-7-mediated protection of these muscle pathologies is discussed in this review. Recent studies have suggested that ACE2 protects against ageing-associated muscle wasting (sarcopenia) through its function to modulate molecules outside of the RAS. Thus, the potential association of sarcopenia with ACE2 and the associated molecules outside of RAS is also presented herein. Further, we introduce the transcriptional regulation of muscle ACE2 by drugs or exercise, and briefly discuss the potential role of ACE2 in the development of COVID-19.

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“…This observation could be explained by SM in early life impacting the metabolome, especially tryptophan metabolism, which then has a causal effect on lean mass. A previous study showed that a tryptophan-deficient diet reduced the skeletal mass in mice [ 23 ]. In addition, an earlier study in pigs revealed that tryptophan deficiency led to a reduced protein synthesis rate in muscles, which recovered upon higher tryptophan intake [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

“…In observational clinical studies, serum tryptophan concentration was found to be positively associated with lean mass in cancer patients with skeletal muscle atrophy [ 23 ]. Furthermore, tryptophan and lysine were positively associated with appendicular lean mass but not with other adiposity-related measures in older black men [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Childhood Malnutrition and Association of Lean Mass with Metabolome and Hormone Profile in Later Life

Gonzales

Lelijveld²,

Bourdon

et al. 2020

Nutrients

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This study aimed to determine the associations of targeted metabolomics and hormone profiles data with lean mass index (LMI), which were estimated using bioelectrical impedance, in survivors of child severe malnutrition (SM) (n = 69) and controls (n = 77) in Malawi 7 years after being treated. Linear associations between individual metabolite or hormone and LMI were determined, including their interaction with nutrition status 7 years prior. Path analysis was performed to determine structural associations. Lastly, predictive models for LMI were developed using the metabolome and hormone profile by elastic net regularized regression (EN). Metabolites including several lipids, amino acids, and hormones were individually associated (p < 0.05 after false discovery rate correction) with LMI. However, plasma FGF21 (Control: β = −0.02, p = 0.59; Case: β = −0.14, p < 0.001) and tryptophan (Control: β = 0.15, p = 0.26; Case: β = 0.70, p < 0.001) were associated with LMI among cases but not among controls (both interaction p-values < 0.01). Moreover, path analysis revealed that tryptophan mediates the association between child SM and LMI. EN revealed that most predictors of LMI differed between groups, further indicating altered metabolic mechanisms driving lean mass accretion among SM survivors later in life.

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Low Levels of Serum Tryptophan Underlie Skeletal Muscle Atrophy

Cited by 26 publications

References 37 publications

Role of Sphingosine 1-Phosphate Signalling Axis in Muscle Atrophy Induced by TNFα in C2C12 Myotubes

Role of Sphingosine 1-Phosphate Signalling Axis in Muscle Atrophy Induced by TNFα in C2C12 Myotubes

ACE2, angiotensin 1-7 and skeletal muscle: review in the era of COVID-19

Childhood Malnutrition and Association of Lean Mass with Metabolome and Hormone Profile in Later Life

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