Xenobiotic and microbe stress promote muscle dysfunction
Description: Metabolism fuels life by extracting useable energy from nutrients allowing the synthesis and maintenance of cellular constituents. Pathogen detection and removal requires a repertoire of sensors and chemical signals that are built and constantly modified using energy consuming processes. These processes are intricately linked in homeostatic responses required for tissue maintenance and repair, but the complexity of integrating immune and metabolic responses dictates the need for addressing fundamental basic science aspects of immunometabolism rather than considering each field alone. Objective 1 aims to understand how xenobiotics engage immune components that promote muscle dysfunction. We propose to build on our discoveries showing that all statins activate an immune response involving the Nod-like Nucleotide-Binding Oligomerization Domain, Leucine Rich Repeat And Pyrin Domain Containing 3 (NLRP3) inflammasome. We will test how NLRP3 acts as a metabolic danger sensor in response to fundamental shifts in muscle cell metabolism induced by statin-mediated lowering protein prenylation, independent of cholesterol. This is important because it may allow for targeting the side-effects of statins without compromising the cholesterol-lowering effects of this widely used drug class. This is applicable to any xenobiotic that targets the mevalonate pathway. We will also investigate how xenobiotics disrupt the Hippo pathway and Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) in muscle cell metabolism. Our exciting preliminary data and international collaboration positions Hippo signalling as a mediator of muscle defects caused by statin-induced lowering of prenylation and NLRP3-driven responses in a muscle cell autonomous manner. This would be the first implication of YAP/TAZ and NLRP3 connection in muscle dysfunction, where we will use newly developed human micro-muscle cultures. Objective 2 aims to understand how commensal bacteria influence endocrine control of muscle mass across the life-course, particularly focussing on muscle functional decline in ageing (i.e. sarcopenia). We have found that germ-free mice have worse sarcopenia. We have identified potential immune receptors that relay bacterial sensing to sarcopenia. Bacterial cell wall sensing by Nod1 is a key immune response that protects mice against sarcopenia. We propose to define how ageing alters sensing of commensal bacteria, which lower growth signals (GH and IGF-1) during sarcopenia. The long-term plan for this research program is to characterize how bacteria and xenobiotics engage specific aspects of host immunity to alter endocrine control of metabolism and muscle homeostasis. This foundational information is required in order to promote evidence-based development of microbiome strategies such as prebiotics, probiotics, and postbiotics and to prevent drug-induced myopathy with next generation drugs that avoid xenobiotic stress responses.
Amount: CA$40,000
Funding type: research
Funder scheme: Discovery Grants Program - Individual
Start date: 2023-04-01
End date: 2024-03-31
Investigator: Jonathan Schertzer
Institution: McMaster University
Funded outputs count: 4
Funder award ID: rgpin-2020-05707
OpenAlex ID: G442722161