PKM2 Determines Myofiber Hypertrophy In Vitro and Increases in Response to Resistance Exercise in Human Skeletal Muscle

Verbrugge, Sander A.J.; Gehlert, Sebastian; Stadhouders, Lian E.M.; Jacko, Daniel; Aussieker, Thorben; Wit, Gerard M.J. de; Vogel, Ilse S.P.; Offringa, Carla; Schönfelder, Martin; Jaspers, Richard T.; Wackerhage, Henning

doi:10.3390/ijms21197062

Cited by 26 publications

(26 citation statements)

References 70 publications

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“…Another pathway that is activated by RE and involved in the regulation of protein synthesis and muscle hypertrophy is the cancer-like reprogramming inducing the synthesis of serine and glycine via PHGDH [ 8 , 73 ]. RE stimulates the expression of pyruvate kinase muscle 2 (PKM2), which in C2C12 myotubes has been shown to induce hypertrophy [ 74 ]. The present results do not show a significant increase in serine and glycine levels; however, this could be due to the fact that these metabolites are immediately incorporated in the synthesized contractile and cytoskeletal proteins.…”

Section: Discussionmentioning

confidence: 99%

Effects of Acute and Chronic Resistance Exercise on the Skeletal Muscle Metabolome

et al. 2022

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Resistance training promotes metabolic health and stimulates muscle hypertrophy, but the precise routes by which resistance exercise (RE) conveys these health benefits are largely unknown. Aim: To investigate how acute RE affects human skeletal muscle metabolism. Methods: We collected vastus lateralis biopsies from six healthy male untrained volunteers at rest, before the first of 13 RE training sessions, and 45 min after the first and last bouts of RE. Biopsies were analysed using untargeted mass spectrometry-based metabolomics. Results: We measured 617 metabolites covering a broad range of metabolic pathways. In the untrained state RE altered 33 metabolites, including increased 3-methylhistidine and N-lactoylvaline, suggesting increased protein breakdown, as well as metabolites linked to ATP (xanthosine) and NAD (N1-methyl-2-pyridone-5-carboxamide) metabolism; the bile acid chenodeoxycholate also increased in response to RE in muscle opposing previous findings in blood. Resistance training led to muscle hypertrophy, with slow type I and fast/intermediate type II muscle fibre diameter increasing by 10.7% and 10.4%, respectively. Comparison of post-exercise metabolite levels between trained and untrained state revealed alterations of 46 metabolites, including decreased N-acetylated ketogenic amino acids and increased beta-citrylglutamate which might support growth. Only five of the metabolites that changed after acute exercise in the untrained state were altered after chronic training, indicating that training induces multiple metabolic changes not directly related to the acute exercise response. Conclusion: The human skeletal muscle metabolome is sensitive towards acute RE in the trained and untrained states and reflects a broad range of adaptive processes in response to repeated stimulation.

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Section: Discussionmentioning

confidence: 99%

Effects of Acute and Chronic Resistance Exercise on the Skeletal Muscle Metabolome

et al. 2022

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“…Recent evidence suggests that, similar to ‘Warburg effect’ in tumours, in hypertrophying skeletal muscle reprogramming towards a more glycolytic metabolism occurs. Glycolytic enzyme pyruvate kinase muscle isoform 2 (PKM2), which is particularly highly expressed in type II myofibres, contributes to the increased hypertrophic potential of type II myofibres ( Verbrugge et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Lack of Tgfbr1 and Acvr1b synergistically stimulates myofibre hypertrophy and accelerates muscle regeneration

Hillege

Shi

Galli

et al. 2022

eLife

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In skeletal muscle, transforming growth factor-β (TGF-β) family growth factors, TGF-β1 and myostatin, are involved in atrophy and muscle wasting disorders. Simultaneous interference with their signalling pathways may improve muscle function, however little is known about their individual and combined receptor signalling. Here we show that inhibition of TGF-β signalling by simultaneous muscle-specific knockout of TGF-β type I receptors Tgfbr1 and Acvr1b in mice, induces substantial hypertrophy, while such effect does not occur by single receptor knockout. Hypertrophy is induced by increased phosphorylation of Akt and p70S6K and reduced E3 ligases expression, while myonuclear number remains unaltered. Combined knockout of both TGF-β type I receptors increases the number of satellite cells, macrophages and improves regeneration post cardiotoxin-induced injury by stimulating myogenic differentiation. Extra cellular matrix gene expression is exclusively elevated in muscle with combined receptor knockout. Tgfbr1 and Acvr1b are synergistically involved in regulation of myofibre size, regeneration and collagen deposition.

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“…We have previously proposed that an elevated glucose uptake during acute resistance exercise provides carbon for synthesizing amino acids, nucleotides, and lipids to support anabolism in hypertrophying muscles. 69 Recently, glycolysis has been shown to limit basal protein synthesis 70 suggesting that glucose metabolism plays a role in the maintenance of muscle mass. The manipulation of several glucose-uptake genes is associated with regulating muscle hypertrophy and glucose uptake in F I G U R E 4 (See caption on next page) concert.…”

Section: Discussionmentioning

confidence: 99%

Genes controlling skeletal muscle glucose uptake and their regulation by endurance and resistance exercise

Verbrugge

Alhusen

Kempin

et al. 2021

J of Cellular Biochemistry

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Exercise improves the insulin sensitivity of glucose uptake in skeletal muscle. Due to that, exercise has become a cornerstone treatment for type 2 diabetes mellitus (T2DM). The mechanisms by which exercise improves skeletal muscle insulin sensitivity are, however, incompletely understood. We conducted a systematic review to identify all genes whose gain or loss of function alters skeletal muscle glucose uptake. We subsequently cross-referenced these genes with recently generated data sets on exercise-induced gene expression and signaling. Our search revealed 176 muscle glucose-uptake genes, meaning that their genetic manipulation altered glucose uptake in skeletal muscle. Notably, exercise regulates the expression or phosphorylation of more than 50% of the glucose-uptake genes or their protein products. This included many genes that previously have not been associated with exercise-induced insulin sensitivity. Interestingly, endurance and resistance exercise triggered some common but mostly unique changes in expression and phosphorylation of glucose-uptake genes or their protein products. Collectively, our work provides a resource of potentially new molecular effectors that play a role in the incompletely understood regulation of muscle insulin sensitivity by exercise.

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PKM2 Determines Myofiber Hypertrophy In Vitro and Increases in Response to Resistance Exercise in Human Skeletal Muscle

Cited by 26 publications

References 70 publications

Effects of Acute and Chronic Resistance Exercise on the Skeletal Muscle Metabolome

Effects of Acute and Chronic Resistance Exercise on the Skeletal Muscle Metabolome

Lack of Tgfbr1 and Acvr1b synergistically stimulates myofibre hypertrophy and accelerates muscle regeneration

Genes controlling skeletal muscle glucose uptake and their regulation by endurance and resistance exercise

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