Sustained CaMKII activation in aging muscle drives contractile dysfunction independently of muscle mass loss, whereas transient CaMKII activation supports performance in young muscle. Inhibiting CaMKII restores function in aged muscle, positioning calcium-dependent signaling dysregulation as a discrete, addressable mechanism in sarcopenia.
Key Points
- CaMKII shifts from adaptive (youth) to maladaptive (age) signaling without hypertrophy.
- Sustained activation impairs contractile force via heme/iron transcriptional remodeling.
- CaMKII inhibition restores aged muscle function and reverses aging transcriptome.
Longevity Analysis
This work reveals a fundamental mismatch between calcium signaling machinery and the aging muscle environment. In youth, exercise-driven calcium transients activate CaMKII briefly—a pattern that sharpens contractile performance. With age, dysregulated calcium handling and redox imbalance sustain CaMKII activity chronically, shifting gene expression toward inflammatory and stress pathways. The key insight is that the problem is not the signaling protein itself, but its sustained engagement in an environment no longer equipped to interpret transient signals correctly. Restoring the ability to decode and regulate these calcium-dependent signals—rather than replacing muscle tissue—partially reverses the functional decline, suggesting that age-related weakness reflects signal mismanagement as much as structural loss. This points toward interventions that restore calcium homeostasis and redox balance as prerequisites for preserving contractile function.
Original published by Wiley Aging Cell, by Michael R. Bene, Tae Chung, Elizabeth D. Luczak, Gabriel Lopez‐Cecetaite, William A. Fountain, Giovanni Rosales‐Soto, Erick Hernández‐Ochoa, Corina Antonescu, Liliana Florea, Seeun J. Jeong, Emily Elassal, Anne Le, Qian‐Li Xue, Ahmet Hoke, Peter M. Abadir, Qinchuan Wang .