Abstract

Sarcopenia is currently considered a systemic condition that goes beyond muscle atrophy to include multi
functional metabolic and cardiovascular dysfunction. The mediators between skeletal muscle loss and entire 
body insulin resistance and increased vulnerability to cardiotoxicity caused by chemotherapy are not clear. We 
hypothesise that mitochondrial-enriched, muscle-secreted extracellular vesicles (EVs) of mtDNA/mitoproteins, 
stress-regulated microRNAs (miR-1/133/206; miR-29 family), and ROS-modified damage-associated molecular 
patterns (DAMPs) are a mitochondrial stress bridge that secretes danger signals from sarcopenic muscle to the 
liver/adipose and heart. EV cargo mechanistically impairs insulin signaling (IRS-1 → PI3K-AKT → GLUT4) and 
cardiomyocyte pre-injury (loss of Δpsm, antioxidant repression, apoptosis), increasing the toxicity of doxoru
bicin. Should this framework be valid, it describes the clustering of sarcopenic patients with metabolic 
dysfunction and disproportional cardiotoxic incidents throughout cancer therapy and places circulating EV cargo 
as an indicator of outcomes and therapeutic interventions.