Modulation of nuclear receptor activity by FHL proteins in the regulation of muscle mass and phenotype
File(s)
Author(s)
Lori, Oritseundede Dede
Type
Thesis
Abstract
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.
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.
Version
Open Access
Date Issued
2015-06
Date Awarded
2015-10
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Kemp, Paul
Sponsor
Biotechnology and Biological Sciences Research Council (Great Britain)
GlaxoSmithKline
Publisher Department
National Heart and Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)