Molecular Metabolism in Cancer and Ageing

Many patients with cancer experience significant metabolic perturbations, such as obesity, loss of muscle mass (cachexia), and dysregulated glucose homeostasis. This project aims to identify the molecular causes of metabolic dysfunctions in cancer with a focus on skeletal muscle and adipose tissue metabolism.

It is well-known that metabolic perturbations, such as obesity and type 2 diabetes increases the risk of developing cancer. Additionally, cancer patients with diabetes or obesity have a much higher risk of death and increased likelihood of cancer recurrence than lean otherwise healthy cancer patients.

In particular, breast cancer, colorectal cancer and lung cancer are associated with impaired metabolic regulation and insulin resistance. Our current research examines the presence and molecular causes of cancer-induced metabolic dysregulation in cell models, mouse models, as well as people with cancer. We investigate the role of physical activity, inflammation, altered fat metabolism, and intracellular molecular signaling in cancer-associated insulin resistance in muscle and fat.

Identification of novel muscle molecules that orchestrate the beneficial effects of exercise

Exercise is the most effective means to prevent non-communicable diseases and promote health. This project identifies novel muscle molecules that orchestrate the beneficial effects of exercise.

Exercise acutely promotes health benefits, such as promoting skeletal muscle glucose uptake, increasing energy utilization, as well as increasing insulin sensitivity in the hours after the exercise bout. In addition to the acute effects of one exercise bout, regular exercise training elicits longer-term benefits, such as increased mitochondria mass and function, amplified capillarization, upregulation of metabolically important proteins, optimization of substrate utilization, and muscle hypertrophy.

All of these adaptations benefit our health. This project investigates the intracellular molecular mechanisms regulated by exercise that mediate these effects with a focus on mitochondrial and muscle mass regulation.

Rho GTPases as novel players in metabolism and muscle mass regulation

Rho GTPases are small molecules that regulate many different processes in the cells, such as cell division and vesicle transport. We are investigating how these molecules are regulated in skeletal muscle and what role they play in muscle metabolism.

We are studying the Rho GTPases expressed in skeletal muscle and has identified Rac1 as a critical regulator of glucose uptake in skeletal muscle, which is a novel player in skeletal muscle insulin resistance in conditions of obesity and type 2 diabetes. This project is further elucidating novel regulators of the Rho GTPase pathways, including the chaperone, GDIa, which is an inhibitor Rho GTPases.

This project is aiming to explore the role for Rho GTPases in skeletal muscle mass and insulin sensitivity regulation and identify their up- and down-stream regulators.

The role of follistatin in muscle hypertrophy and insulin sensitivity

Follistatin is well-known to promote muscle hypertrophy. We are trying to understand how folliatatin additionally influences whole-body metabolic regulation and skeletal muscle insulin sensitivity.

Circulating follistatin is increased in response to exercise and fasting. Follistatin neutralizes members of the TGF-β superfamily, such as myostatin and activin A, promoting muscle hypertrophy.

Our research focuses on examining the role for follistatin in muscle metabolism and insulin sensitivity. We are exploring how type 2 diabetes and metabolic surgery influences circulating follistatin and its molecular effects in skeletal muscle. We use mouse models to explore the molecular signaling pathways by which follistatin improves insulin sensitivity and its role in metabolism.