Sarcopenia is currently considered a systemic condition that goes beyond muscle atrophy to include multifunctional 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 doxorubicin. 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.