Mitochondria-Inflammation crosstalk and EXercise-induced pathways in cachexIA

Cancer cachexia (CC) affects 50-80% of patients with cancer and is characterized by accelerated loss of muscle mass, which is directly linked to reduced quality of life, treatment toxicity, and lower survival. With no pharmacological treatment options, key to improving life expectancy is to understand the molecular determinants of CC, however, these are poorly defined. Mitochondrial dysfunction and inflammation can cause muscle atrophy and are considered as emerging hallmarks of CC. Exercise is the most potent approach to improve mitochondrial and muscle function, and to reduce inflammation, yet, implementing it in CC is challenging because of fatigue and pain of patients with cancer. Elucidating the molecular underpinnings of exercise’s beneficial effects represents a major scientific challenge and an untapped opportunity for medical exploitation. In this regard, unpublished data from my host lab show that muscle protein levels of the mitochondrial (mt) RNA stabilizer LRPPRC (Leucine-rich PPR motif-containing protein) are induced upon exercise and reduced in cachectic muscles. Thus, mtRNA metabolism could be a new target for CC. mtRNA metabolism is key to maintain levels of mtDNA-encoded proteins to promote mitochondrial function. Yet LRPPRC´s role in muscle mitochondrial function and CC is unexplored. I hypothesize that reduced LRPPRC is key in CC-associated muscle mitochondrial dysfunction and inflammation. Stimulation of LRPPRC could promote exercise-like benefits, establishing a new pharmacological target for CC. I aim to determine the molecular link between mitochondrial dysfunction, inflammation, and muscle atrophy in preclinical CC models and patients with CC. I will unravel the molecular pathways involved in LRRPRC’s exercise-induced effects and I will appraise LRPPRC’s therapeutic potential in CC. Results have the potential to provide crucial insights on the molecular events underlying CC and likely identify new pharmacological strategies to tackle it.