A Piezo1/KLF15/IL-6 axis mediates immobilization-induced muscle atrophy

Although immobility is a common cause of muscle atrophy, the mechanism underlying this causality is unclear. We here show that Kruppel-like factor 15 (KLF15) and IL-6 are upregulated in skeletal muscle of limb-immobilized mice and that mice with KLF15 deficiency in skeletal muscle or with systemic IL-6 deficiency are protected from immobility-induced muscle atrophy. A newly developed [Ca.sup.2+] bioimaging revealed that the cytosolic [Ca.sup.2+] concentration ([[Ca.sup.2+]].) of skeletal muscle is reduced to below the basal level by immobilization, which is associated with the downregulation of Piezo1. Acute disruption of Piezol in skeletal muscle induced Klf15 and Il6 expression as well as muscle atrophy, which was prevented by antibodies against IL-6. A role for the Piezo1/KLF15/IL-6 axis in immobility-induced muscle atrophy was validated in human samples. Our results thus uncover a paradigm for [Ca.sup.2+] signaling in that a decrease in [[Ca.sup.2+]] from the basal level triggers a defined biological event.
Introduction A decline in skeletal muscle mass can lead to a variety of detrimental conditions and a consequent shortening of life (1). Although many pathological conditions--including neuromuscular, cardiovascular, metabolic, inflammatory, [...]