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Title: The role of C-peptide in skeletal muscle
Author: Essid, Sumia Mohamed
ISNI:       0000 0004 5918 940X
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2016
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Over the past 20 years, considerable evidence has accumulated indicating that proinsulin C-peptide plays a crucial role in the functions of a number of tissues. In type 1 diabetes mellitus (T1DM) deficiency of C-peptide along with insulin is associated with development of impairment of skeletal muscle functions such as growth, and regenerative and physical capacity, and is thought to be an important contributor to increased morbidity and mortality and decreased quality of life in T1DM. This thesis tested the hypothesis that C-peptide activates key signalling pathways in myoblasts (muscle progenitor cells) thus promoting transport of glucose and amino acids, and exerting growth and cell survival effects. This was tested by investigating the effects of C-peptide on the L6 rat myoblast cell line under serum-starved conditions. C-peptide at physiological concentrations as low as 0.03 nM, exerted stimulatory effects on intracellular signalling pathways MAP Kinase (ERK1/2) and Akt. The Akt effect was abolished by pertussis Toxin (PTX) suggesting that C-peptide acted through a G-protein coupled receptor. In spite of these clear signalling effects, C-peptide alone had no effect on cell growth, protein content, glucose transport or system A amino acid transport; although as little as 0.03 nM did enhance the previously well-documented pH sensitivity of system A transport. Even though C-peptide alone had no detectable effect on cell survival, when apoptosis was induced by the cholesterol-lowering drug simvastatin (as a model for statin-induced myopathy), 3 nM C-peptide potently suppressed the apoptotic effect through a PTX-sensitive pathway. Simvastatin strongly impaired Akt signalling and stimulated reactive oxygen species production; and both of these effects were abolished by C-peptide, suggesting that Akt signalling and oxidative stress were important factors in statin-induced apoptosis in L6 myoblasts. The findings demonstrated in this thesis suggest that C-peptide exerts an important protective effect against death signalling in myoblasts. Therefore in T1DM, deficiency of C-peptide may contribute to myopathy by rendering myoblast-like progenitor cells (involved in muscle regeneration) more susceptible to the toxic effects of insults such as simvastatin.
Supervisor: Bevington, Alan ; Brunskill, Nigel Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available