Debruin, Danielle A (2021) A Pre-clinical Evaluation of Novel Combination Treatments to Alleviate Skeletal Muscle Loss and Dysfunction. PhD thesis, Victoria University.

Abstract

Preserving skeletal muscle mass is essential for maintaining optimal health throughout the lifespan. Altered skeletal muscle protein and energy metabolism, which typically occurs during the ageing process, leads to muscle degeneration, reduced strength and increased total body fat. As a result, the risk factor for chronic co-morbidities increases, highlighting the importance of preventing and/or treating decreased skeletal muscle mass and strength. While exercise, especially resistance training, is effective in slowing mass and strength loss, the search for appropriate drug therapies remains paramount with respect to global health cost and burden. In addition to this, pre-clinical evaluation of conditions like sarcopenia - the age-related loss of skeletal muscle mass and function - typically require older animals, which are timely and costly. Besides simply aged or genetically modified, there seems to be a lack of accelerated animal models of ageing that recapitulate the physiological underpinnings of conditions like sarcopenia. Thus, part of this thesis was to develop a rapid model of sarcopenia in a young mouse by combining hind limb casting (to induce rapid muscle atrophy) and castration-dependent androgen depletion (to mimic loss of testosterone seen with age). We found that these mice elicited a similar loss in muscle mass compared to middle aged ‘peri-sarcopenic’ mice and had significant detriments in slow-twitch muscle force. With the changes in the model demonstrating a loss in mass and strength, we attempted to correct this by applying a novel combination treatment which was established through three pilot studies. This combination treatment was effective at increasing muscle mass and strength; and decreasing fatigue in slow twitch muscle of healthy mice, strengthening its application in our atrophy model. Therefore, results from this thesis explored the robustness of a new animal model of sarcopenia and that our innovative combination treatment could potentially combat the problems associated with various skeletal muscle conditions.

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