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Title: Modulation of nuclear receptor activity by FHL proteins in the regulation of muscle mass and phenotype
Author: Lori, Oritseundede Dede
ISNI:       0000 0004 6495 4655
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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Skeletal muscle wasting or atrophy is an important public health problem associated with aging and a number of mortality related diseases including, chronic obstructive pulmonary disease and cancer. Muscle wasting is a reflection of an imbalance in the regulation of muscle mass and phenotype and is controlled by a number of factors in mammals including the level of physical activity, hormonal status and the activity of signaling molecules and pathways. The aim of this thesis was therefore to understand better the muscle wasting pathway by focusing on the four-and-a-half lim protein family of which one member has been shown to be a key regulator of muscle mass (FHL1). Results showed that FHL1 could cause an increase and decrease in myotube size in a skeletal muscle cell line by increasing hormone activity through activating the AR and GR respectively. Furthermore over-expression of FHL1 in the tibialis anterior (TA) muscle of mice caused hypertrophy in the absence of dexamethasone treatment, however this muscle phenotype was negated by treatment of the mice with dexamethasone. Another family member named FHL3, investigated due to its high expression in skeletal muscle was found to alter AR and GR activity in vitro, however these observations did not translate to in vivo results as, unlike the effects of FHL1 on muscle size, there was no increase in the size of TA muscles over-expressing FHL3 nor did dexamethasone treatment of FHL3 expressing muscles cause a significant reduction in muscle size compared to TA muscles extracted from saline treated muscles. Together these data support FHL1 as a key regulator of skeletal muscle mass and phenotype.
Supervisor: Kemp, Paul Sponsor: Biotechnology and Biological Sciences Research Council ; GlaxoSmithKline
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral