Characterization of the role of Irisin in skeletal muscle growth and repair
Musarrat Maisha Reza
Date of Issue2017-08-07
School of Biological Sciences
Exercise stimulates the expression of PPAR-γ co-activator I-α (PGC I-α), which in turn increases the levels of the myokine, Irisin. Irisin is synthesized as part of a 209 amino acid (aa) long precursor protein, Fibronectin Type III Domain Containing Protein 5 (FNDC5), which is proteolytically cleaved at the C terminal to give rise to the 112 amino acid long Irisin protein. Irisin induced upon exercise, promotes browning of white adipose tissue through binding to CD 13 7+ precursor cells, resulting in increased energy expenditure, reduced adiposity and improved insulin sensitivity. A novel function of Irisin on skeletal muscle has been reported in this thesis. Recombinant Irisin protein induced a number of pro-myogenic and exercise response genes in myotubes. Moreover, treatment of C2C 12 myoblasts with recombinant murine Irisin protein resulted in increased myoblast proliferation and fusion, leading to increased myogenic differentiation. Expression analysis of myoblast differentiation markers showed upregulation of Myosin Heavy Chain (MHC) in response to Irisin treatment, which validated the increased differentiation noted. Moreover, the primary fusion marker, Myomaker was also shown to be upregulated by Irisin treatment. In addition, evidence presented in this thesis revealed that the increased myogenic differentiation observed following Irisin treatment is, at least in part, due to IL6. These data reveal that Irisin positively regulates myogenesis through enhancing myoblast growth, differentiation and fusion. Mice injected with recombinant mUrIne Irisin displayed increased muscle weights, distinct hypertrophy in un-injured muscle and enhanced grip strength, further supporting the pro-myogenic function of Irisin. Mechanistically, Irisin promoted skeletal muscle hypertrophy, through increasing protein synthesis and inhibiting protein degradation pathways. Expression analysis confirmed that Irisin activates the protein synthesis pathways via Akt, Erk and MAPK activation. In addition, Irisin inhibits the protein degradation pathway by reducing the expression of E3 ubiquitin ligases, Atrogin-I and MuRF-I.