Muscle metabolism and intercellular crosstalk - effects of in vitro exercise and changes in muscle size

Abstract

Skeletal muscles have an active role in the regulation of the whole-body metabolism in health and disease. Maintenance of skeletal muscle mass is important for everyday life as well as for better prognosis against muscle wasting diseases, such as cancer cachexia. Along with its role in the wasting conditions, skeletal muscle is also a key tissue in exercise. In addition to traditional endocrine organs, such as pancreas, skeletal muscles can also produce and release signaling molecules, collectively known as exerkines, that finetune metabolism in the recipient cells and tissues. The purpose of this dissertation was to examine skeletal muscle physiology, metabolism, and secretome in response to changes in muscle size and to muscle cell contractions. To address these interactions, both animal and cell models were used. More specifically, muscle wasting induced by the C26 colon carcinoma cells in vivo and myostatin in vitro were used to model muscle atrophy. The blockade of myostatin and activins, negative regulators of muscle size, was used to reverse muscle wasting in vivo. The direct skeletal muscle-specific effects of myostatin were studied using muscle cells. Muscle cell contractions induced by exercise-like electrical pulse stimulation in vitro were used to mimic in vivo exercise. The main findings of this dissertation were that cancer greatly disturbed skeletal muscle and serum metabolomes. These disturbances could not be rescued by the reversal of muscle wasting using myostatin and activin blocker. Myostatin had expected effects on signaling in the myoblasts, but the differentiation of the murine C2C12 cells into myotubes decreased this response. Human muscle cells appeared to maintain their responsiveness to myostatin better, also after differentiation. Myotube contractions induced many expected, but also newly detected intra- and extracellular changes at the metabolome and transcriptome levels. Based on these omics-analyses, the observed changes were mainly related to energy metabolism, contractility, and inflammatory response. This dissertation provides novel insights into skeletal muscle and exercise research that may improve development of better in vivo and especially in vitro models to study not only skeletal muscle physiology per se, but also the mediators and the mechanisms of intercellular crosstalk in different conditions.