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Skeletal muscle regulatory factors with alterations in muscle mass

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(Dissertation) Ph.D.
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Given that maintenance of skeletal muscle mass is essential for overall health, functionality and quality of life, it is critical to elucidate the fundamental mechanisms underlying the maintenance of muscle mass which likely vary as a function of muscle status (i.e. healthy or diseased). This thesis examined key skeletal muscle regulatory factors (smRF’s) that are known to affect skeletal muscle mass, including components of the PI3K/Akt and MAPK(ERK) pathways, calcineurin, the myogenic regulatory factors and myostatin, following administration of a b2-adrenergic agonist, Clenbuterol, and with progressive denervation. Although it is known that Clenbuterol induces hypertrophy and attenuates atrophy of skeletal muscle, its mechanism of action is unclear. In this thesis, I have demonstrated that Clenbuterol induces PKA-independent stimulation of smRF’s (cAMP, p-Akt, p-ERK), and additional phospho-kinases (PKCa, PAK1/2/3, FAK and Pyk2) that are also thought to be involved in regulating muscle mass. These changes occur relatively rapidly, often within 10 minutes of administration. Using a G93A mouse model of progressive denervation, I found an up-regulation of smRF’s involved in growth/survival (Akt, calcineurin, ERK1/2), and decreases in the myogenic regulatory factor, MyoD, in skeletal muscle of these mice. These alterations occurred in conjunction with the onset of later-stage (i.e. severe) symptoms but prior to significant muscle atrophy. I was therefore interested in determining if Clenbuterol would attenuate the onset of disease symptoms and muscle atrophy accompanying the progressive denervation by altering these smRFs. Akt and MyoD levels in the G93A mouse were similar to wild-type muscle after six weeks of Clenbuterol treatment. Clenbuterol also attenuated the progression of symptoms in G93A mice which may account for the levels of smRF’s observed. Increases in G93A mouse body mass, improved motor coordination (RotoRod) and strength (PaGE, females only) were also observed with Clenbuterol treatment without significant increases in muscle mass. This thesis suggests that alterations in smRF’s, including the PI3K/Akt and MAPK(ERK) pathways, calcineurin, and the myogenic regulatory factors occur prior to any observable changes in muscle mass. Identification of these muscle-specific factors has clinical relevance for the characterization and treatment of skeletal muscle atrophy associated with chronic diseases.
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