2020

Hentilä, Jaakko

Proteostasis results from an equilibrium between the synthesis of functional and degradation of dysfunctional proteins. It is regulated by biological processes, including unfolded protein response (UPR) and autophagy. UPR tries to relieve endoplasmic reticulum (ER) stress that results from protein misfolding in ER and autophagy degrades cellular organelles and proteins. Autophagy and UPR have a pivotal role for skeletal muscle function, but the current knowledge how they are regulated by different conditions influencing muscle quality is limited. This thesis elucidated the effects of muscle wasting, hypertrophy and exercise on the markers of autophagy and UPR by measuring protein and mRNA expression in skeletal muscle. To elucidate the effects of muscle wasting, mdx and colon carcinoma 26 (C26) tumor-bearing mice were used to study muscular dystrophy and cancer cachexia, respectively. Additionally, the effects of muscle hypertrophy induced by blocking activin receptor ligands in healthy, cancer cachectic and dystrophic mdx mice were examined. Voluntary wheel running was also studied in mdx mice. In addition to experimental animal models, the acute (1 h and 48 h) and long-term effects (21 weeks) of resistance exercise and training (RE and RT, respectively) in young (26 ± 4 years) and older (61 ± 6 years) previously untrained men were elucidated. Furthermore, the effects of 20-week experimental training period (EX), in which strength training was integrated with sprint training, in master sprinter men (40–76 years) were studied. The main results of this thesis were that UPR is induced by muscular dystrophy, as well as by a single RE bout in young and older men. Additionally, muscle hypertrophy induced by activin receptor ligand blocking increased UPR markers in healthy mice, while this increase in UPR markers was not observed in muscle hypertrophy induced by the 21-week RT period in young and older men. Autophagosome content, marked by lipidated LC3 protein (LC3II), was increased in C26 cancer cachexia and by RE and RT in previously untrained young men, as well as in masters sprinters conducting long-term strength training in conjunction with sprint training. These results indicate that, as an adaptation to muscle hypertrophy, wasting and exercise UPR and autophagy are regulated distinctly in skeletal muscle depending on the context. These results may be applied in the future as a scientific basis to develop new strategies to prevent and treat muscle wasting and in offering evidence based exercise recommendations.