Circulating factors affecting skeletal muscle metabolism

The overall aim of this doctoral thesis was to study the role of circulating factors in modulating skeletal muscle metabolism. To this end, we investigated two different scenarios: Type 2 diabetes, which is characterised by impaired skeletal muscle metabolism and reduced insulin sensitivity, and exercise training, which induces various adaptations in skeletal muscle that ultimately improve insulin sensitivity and substrate handling.

Specifically, the aims of the studies presented in the thesis were to determine whether an increase in the circulating levels of the amino acid glutamine improves whole-body and skeletal muscle metabolism and insulin sensitivity (Study I), and whether three weeks of endurance exercise training alters the microRNA cargo of circulating extracellular vesicles (Study II).

Study I revealed that increasing circulating levels of the amino acid glutamine improves whole-body glucose homeostasis and skeletal muscle insulin action. This effect was attributed to the modulation of inflammatory gene expression and the downregulation of Growth factor receptor-bound protein (GRB10), an inhibitor of insulin signalling. Study II found that three weeks of supervised endurance exercise training changes the microRNA content of serumderived extracellular vesicles, specifically increasing the content of microRNA miR-136-3p. microRNA miR-136-3p increases glucose uptake, oxygen consumption rate and extracellular acidification rate in human skeletal muscle cells. In skeletal muscle, miR-136-3p directly targets NRDC, an exercise- and inactivity-responsive gene, although the metabolic effects induced by mir-136-3p are not solely mediated through the silencing of NRDC.

List of scientific papers

I. Dollet L, Kuefner M, Caria E, Rizo-Roca D, Pendergrast L, Abdelmoez AM, Karlsson HKR, Björnholm M, Dalbram E, Treebak JT, Harada J, Naslund E, Rydén M, Zierath JR, Pillon NJ, Krook A. Glutamine regulates skeletal muscle immunometabolism in Type 2 Diabetes. Diabetes. 2022;71:624-636.
https://doi.org/10.2337/db20-0814

II. Katayama M, Caria E, Yagüe Sanz A, Barrès R, Caidahl K, Wiklander OPB, El-Andaloussi S, Zierath JR, Krook A. Exercise-training-induced exosomal miR-136-3p modulates mitochondrial function by targeting NRDC in human skeletal muscle. [Manuscript]