Gut microbes, ageing & organ function:a chameleon in modern biology?

All species, including humans, are cohabited by a myriad of microbial species, which massively influences body function in a diet-, exercise- and age-dependent manner. The microbiome composition differs between individuals, partly due to the polymorphic immune system, as well as the environment, making the microbe-host interplay unique in each one of us. Ageing is a gradual loss of function in part due to reduced repair mechanisms and accumulation of tissue damage through mechanisms largely unknown. Accumulating evidence suggests that our indigenous microbes, a known major regulator of human physiology, are also connected to regulate the ageing process through signalling pathways and metabolites though the biological mechanisms are unknown. At an ageing meeting in Singapore in 2018, investigators discussed the current understanding of microbe regulation and its impact on healthy ageing. This review summarizes the highlights from the meeting and conveys some of the new ideas that emerged around gut microbes and the biology of ageing. While highly speculative, an idea emerged in which gut microbes constantly respond and evolve to environmental cues, as part of an ageing process, thus serving as a second messenger to support and attenuate organ decline in a diet-, gender- and age-dependent manner

Irisin treatment improves healing of dystrophic skeletal muscle

Background: Irisin is an exercise induced myokine that is shown to promote browning of adipose tissue and hence, increase energy expenditure. Furthermore, our unpublished results indicate that Irisin improves myogenic differentiation and induces skeletal muscle hypertrophy. Since exercise induced skeletal muscle hypertrophy improves muscle strength, we wanted to investigate if ectopic injection of Irisin peptide improves skeletal muscle function in a mouse model of muscular dystrophy. This utility of Irisin peptide is yet to be studied in animal models. Methods: In order to test this hypothesis, we expressed and purified recombinant murine Irisin peptide from E. coli. Three- to six-week-old male mdx mice were injected IP with either vehicle (dialysis buffer) or Irisin recombinant peptide for two or four weeks, three times-a-week. Results: Irisin injection increased muscle weights and enhanced grip strength in mdx mice. Improved muscle strength can be attributed to the significant hypertrophy observed in the Irisin injected mdx mice. Moreover, Irisin treatment resulted in reduced accumulation of fibrotic tissue and myofiber necrosis in mdx mice. In addition, Irisin improved sarcolemmal stability, which is severely compromised in mdx mice. Conclusion: Irisin injection induced skeletal muscle hypertrophy, improved muscle strength and reduced necrosis and fibrotic tissue in a murine dystrophy model. These results demonstrate the potential therapeutic value of Irisin in muscular dystrophy

Irisin is a pro-myogenic factor that induces skeletal muscle hypertrophy and rescues denervation-induced atrophy

Exercise induces expression of the myokine irisin, which is known to promote browning of white adipose tissue and has been shown to mediate beneficial effects following exercise. Here we show that irisin induces expression of a number of pro-myogenic and exercise response genes in myotubes. Irisin increases myogenic differentiation and myoblast fusion via activation of IL6 signaling. Injection of irisin in mice induces significant hypertrophy and enhances grip strength of uninjured muscle. Following skeletal muscle injury, irisin injection improves regeneration and induces hypertrophy. The effects of irisin on hypertrophy are due to activation of satellite cells and enhanced protein synthesis. In addition, irisin injection rescues loss of skeletal muscle mass following denervation by enhancing satellite cell activation and reducing protein degradation. These data suggest that irisin functions as a pro-myogenic factor in mice

Making environmental and health equal, diverse, and inclusive: Reflections from a Centre of Environment and Human Health (REACH)

The REACH Project has allowed the Centre to take initial stock of current and future research and training as well as the Centre culture through a lens of decolonisation and anti-racism. The Reflections from a Centre of Environment and Human Health (REACH) Project was funded under the Natural Environment Research Council (NERC) Making environment and health equal, diverse, and inclusive Programme

Characterization of the role of Irisin in skeletal muscle growth and repair

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.​Doctor of Philosophy (SBS