Evidence of myomiR regulation of the pentose phosphate pathway during mechanical load‐induced hypertrophy

Valentino, Taylor; Figueiredo, Vandré Casagrande; Mobley, C. Brooks; McCarthy, John J.; Vechetti, Ivan J.

doi:10.14814/phy2.15137

Cited by 14 publications

(12 citation statements)

References 78 publications

(100 reference statements)

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“…A large proportion of downregulated genes were related to oxidative metabolism (Figure 1C) (Table S3). This repressed gene signature could contribute to a "Warburg effect" that occurs during rapid overload-induced muscle hypertrophy, marking a shift towards "aerobic glycolysis" for rapid biomass accumulation (38)(39)(40)(41). Consistent with our prior murine studies (19,25,26) and human resistance exercise time course data (23), Myc was higher after overload (Log2FC=2.0, adj.…”

Section: Resultssupporting

confidence: 83%

“…MYH2 protein and oxidative fiber proportion increases after prolonged muscle overload (99). MYC-mediated and early Myh2 downregulation during overload may relate to an acute glycolytic preference during rapid hypertrophy (38).…”

Section: Discussionmentioning

confidence: 99%

“…Type 2a myosin is associated with oxidative metabolism in murine muscle (79,80). Lower Myh2 may be part of a Warburg-like program that accompanies rapid muscle growth (38,39). Reverb𝛼 (Nr1d1, Log2FC=-1.36, adj.…”

Section: Experiments 5: the Myc-controlled Transcriptome In Plantaris...mentioning

confidence: 99%

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Multi-transcriptome analysis following an acute skeletal muscle growth stimulus yields tools for discerning global and MYC regulatory networks

Murach¹,

Liu²,

Jude³

et al. 2022

Journal of Biological Chemistry

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Section: Resultssupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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Multi-transcriptome analysis following an acute skeletal muscle growth stimulus yields tools for discerning global and MYC regulatory networks

Murach¹,

Liu²,

Jude³

et al. 2022

Journal of Biological Chemistry

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“…In a more recent publication, the authors confirmed that an overload roughly doubled plantaris glucose uptake, increased lactate secretion by ≈ 50% (but no effect on glycolytic flux) and activated the pentose phosphate pathway as evidenced for example by increased glucose-6 phosphate dehydrogenase protein levels [30]. Moreover, we recently demonstrated that the expression of G6pd, which encodes glucose-6 phosphate dehydrogenase, the rate-limiting gene of the pentose phosphate pathway, is upregulated together with other genes of the pentose phosphate pathway in mechanically overloaded mouse plantaris muscles [31]. The pentose phosphate pathway is active in cancer [32] and synthesises nucleotides for DNA, RNA and ribosome biogenesis (ribosomes primarily consist of ribosomal RNA).…”

Section: Is There Evidence That Metabolicmentioning

confidence: 89%

“…An unbiased RNA interference screen of metabolic genes has identified Phgdh as an enzyme that limits proliferation of breast cancer cells [47]. In muscle, Phgdh expression increases in mouse muscle that hypertrophies after synergist ablation [20,31]. Phgdh expression also transiently increases in response to β 2 -agonist stimulation [48] but not after human resistance exercise [21].…”

Section: Is There Evidence That Metabolicmentioning

confidence: 99%

Does a Hypertrophying Muscle Fibre Reprogramme its Metabolism Similar to a Cancer Cell?

et al. 2022

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In 1924, Otto Warburg asked “How does the metabolism of a growing tissue differ from that of a non-growing tissue?” Currently, we know that proliferating healthy and cancer cells reprogramme their metabolism. This typically includes increased glucose uptake, glycolytic flux and lactate synthesis. A key function of this reprogramming is to channel glycolytic intermediates and other metabolites into anabolic reactions such as nucleotide-RNA/DNA synthesis, amino acid-protein synthesis and the synthesis of, for example, acetyl and methyl groups for epigenetic modification. In this review, we discuss evidence that a hypertrophying muscle similarly takes up more glucose and reprogrammes its metabolism to channel energy metabolites into anabolic pathways. We specifically discuss the functions of the cancer-associated enzymes phosphoglycerate dehydrogenase and pyruvate kinase muscle 2 in skeletal muscle. In addition, we ask whether increased glucose uptake by a hypertrophying muscle explains why muscularity is often negatively associated with type 2 diabetes mellitus and obesity.

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Skeletal muscle hypertrophy rewires glucose metabolism: An experimental investigation and systematic review

Baumert,

Mäntyselkä,

Schönfelder

et al. 2024

J cachexia sarcopenia muscle

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BackgroundProliferating cancer cells shift their metabolism towards glycolysis, even in the presence of oxygen, to especially generate glycolytic intermediates as substrates for anabolic reactions. We hypothesize that a similar metabolic remodelling occurs during skeletal muscle hypertrophy.MethodsWe used mass spectrometry in hypertrophying C2C12 myotubes in vitro and plantaris mouse muscle in vivo and assessed metabolomic changes and the incorporation of the [U‐13C6]glucose tracer. We performed enzyme inhibition of the key serine synthesis pathway enzyme phosphoglycerate dehydrogenase (Phgdh) for further mechanistic analysis and conducted a systematic review to align any changes in metabolomics during muscle growth with published findings. Finally, the UK Biobank was used to link the findings to population level.ResultsThe metabolomics analysis in myotubes revealed insulin‐like growth factor‐1 (IGF‐1)‐induced altered metabolite concentrations in anabolic pathways such as pentose phosphate (ribose‐5‐phosphate/ribulose‐5‐phosphate: +40%; P = 0.01) and serine synthesis pathway (serine: −36.8%; P = 0.009). Like the hypertrophy stimulation with IGF‐1 in myotubes in vitro, the concentration of the dipeptide l‐carnosine was decreased by 26.6% (P = 0.001) during skeletal muscle growth in vivo. However, phosphorylated sugar (glucose‐6‐phosphate, fructose‐6‐phosphate or glucose‐1‐phosphate) decreased by 32.2% (P = 0.004) in the overloaded muscle in vivo while increasing in the IGF‐1‐stimulated myotubes in vitro. The systematic review revealed that 10 metabolites linked to muscle hypertrophy were directly associated with glycolysis and its interconnected anabolic pathways. We demonstrated that labelled carbon from [U‐13C6]glucose is increasingly incorporated by ~13% (P = 0.001) into the non‐essential amino acids in hypertrophying myotubes, which is accompanied by an increased depletion of media serine (P = 0.006). The inhibition of Phgdh suppressed muscle protein synthesis in growing myotubes by 58.1% (P < 0.001), highlighting the importance of the serine synthesis pathway for maintaining muscle size. Utilizing data from the UK Biobank (n = 450 243), we then discerned genetic variations linked to the serine synthesis pathway (PHGDH and PSPH) and to its downstream enzyme (SHMT1), revealing their association with appendicular lean mass in humans (P < 5.0e‐8).ConclusionsUnderstanding the mechanisms that regulate skeletal muscle mass will help in developing effective treatments for muscle weakness. Our results provide evidence for the metabolic rewiring of glycolytic intermediates into anabolic pathways during muscle growth, such as in serine synthesis.

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Evidence of myomiR regulation of the pentose phosphate pathway during mechanical load‐induced hypertrophy

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 14 publications

References 78 publications

Multi-transcriptome analysis following an acute skeletal muscle growth stimulus yields tools for discerning global and MYC regulatory networks

Multi-transcriptome analysis following an acute skeletal muscle growth stimulus yields tools for discerning global and MYC regulatory networks

Does a Hypertrophying Muscle Fibre Reprogramme its Metabolism Similar to a Cancer Cell?

Skeletal muscle hypertrophy rewires glucose metabolism: An experimental investigation and systematic review

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