Study of the role of skeletal muscle-derived IL-6 in aging and sarcopenia

Aging is a complex, gradual, and irreversible biological process characterized by the accumulation of molecular and cellular damage over time, leading to a progressive decline in physiological functions and increased vulnerability to disease and death. One major hallmark of aging is sarcopenia, characterized by the progressive loss of skeletal muscle mass and function. Chronic low-grade inflammation, particularly involving interleukin-6 (IL-6), plays a central role in this condition. IL-6 is a multifunctional cytokine involved in immune regulation, inflammation, and metabolism. While it is produced by multiple tissues, the specific contribution of skeletal muscle-derived IL-6 to age-related muscle decline remains unclear. This thesis explores the role of skeletal muscle-derived IL-6 in a context of aging and sarcopenia using aged mouse models with a tamoxifen-inducible, muscle-specific knockout of both Opa1 and IL6 (iOpa1-Il6 mDKO). This approach allows us to investigate the contribution of skeletal muscle to inflammatory processes. Remarkably, muscle-specific deletion of IL-6 led to increased survival, reduced systemic inflammation, and reduced cellular senescence in transgenic mice. However, IL-6 ablation also resulted in diminished muscle mass, function, and impaired calcium homeostasis. Indicating that IL-6, while promoting chronic inflammation, may also be essential for maintaining muscle physiology during aging. These findings reveal a dual role for skeletal muscle-derived IL-6 in aging: as both a pro-inflammatory mediator and a necessary factor for muscle maintenance. Understanding this balance may inform future strategies to mitigate sarcopenia without impairing muscle integrity.