Sustained Activation of CaMKII Promotes Skeletal Muscle Contractile Dysfunction in Aging
TL;DR
It is shown that CaMKII protein abundance is increased in aged mouse skeletal muscle and that sustained CaMKII activation in young muscle is sufficient to impair contractile function before substantial atrophy develops and, with prolonged activation, to promote progressive muscle loss.
Abstract
Sarcopenia, the age‐related loss of muscle strength and mass, contributes to adverse health outcomes in older adults. Exercise engages calcium (Ca2+)‐ and redox‐dependent signaling pathways that enhance muscle performance and adaptation, whereas aging disrupts Ca2+ and redox homeostasis. CaMKII is a key transducer of both signals, raising the possibility that sustained CaMKII signaling becomes maladaptive with aging. Here, we show that CaMKII protein abundance is increased in aged mouse skeletal muscle and that sustained CaMKII activation in young muscle is sufficient to impair contractile function before substantial atrophy develops and, with prolonged activation, to promote progressive muscle loss. Sustained CaMKII activation also disrupted mitochondrial organization and shifted the young‐muscle transcriptome toward an aged profile characterized by inflammatory and stress‐response pathways. Inhibiting canonical NF‐κB signaling partially preserved contractile force during prolonged CaMKII activation without preserving muscle mass, and mediation analysis implicated heme/iron‐related transcriptional remodeling in the muscle‐mass‐independent decline in force. Conversely, expression of CN19o, a peptide inhibitor of CaMKII, in aged muscle improved contractile function and shifted the transcriptome away from an aging‐associated profile without inducing hypertrophy. Together, these findings identify sustained CaMKII signaling as a contributor to age‐associated muscle dysfunction and support a context‐dependent shift from adaptive CaMKII signaling in youth to maladaptive signaling in aging, consistent with antagonistic pleiotropy.