Contribution of Skeletal Muscle-Derived IL-6 to Aging and Sarcopenia

Mitochondrial dysfunction is a key contributor to aging and sarcopenia. Research from Marco Sandri’s lab demonstrated that acute, muscle-specific deletion of the mitochondrial fusion protein Opa1 in adult mice (iOpa1 mKO) induces severe muscle loss, a systemic inflammatory response, precocious epithelial senescence, and premature death. This phenotype is driven by a dramatic upregulation and secretion of muscle-derived Fibroblast Growth Factor 21 (FGF21). Remarkably, simultaneous muscle-specific ablation of both Opa1 and Fgf21(iOpa1/Fgf21 mDKO) completely rescues the aging phenotype and prevents early mortality. Interestingly, blocking mitochondrial fission alone (iDrp1 mKO) or concurrently with fusion (iOpa1/Drp1 mDKO) further elevates FGF21 levels without causing premature senescence or lethality. This indicates that FGF21 requires synergistic, complementary factors to drive the iOpa1 mKO phenotype. Furthermore, sterile inflammation and elevated pro-inflammatory cytokines, specifically muscle-derived IL-6, were prominent in iOpa1 mKO mice but absent in fission-deficient models. To determine the direct contribution of muscle-derived inflammation, we generated inducible, muscle-specific Opa1/IL-6 double-knockout mice (iOpa1/IL-6 mDKO). Notably, while the muscle-specific deletion of IL-6 significantly prolonged survival, attenuated systemic inflammation, and diminished cellular senescence, it paradoxically induced muscle atrophy in these transgenic animals. All the results obtained suggest that IL-6 is a key mediator of mitochondrial dysfunction, playing a central role in aging-related inflammation and sarcopenia. However, IL-6 has also negatively impacted muscle homeostasis, highlighting IL-6’s important role in muscle adaptation to sarcopenic changes. To investigate the role of muscle-derived IL-6 during physiological aging in a murine model Marco Sandri’s laboratory developed a tamoxifen-inducible, muscle-specific IL-6 knockout (mKO) mouse. Crucially, unlike the severe iOpa1/IL-6 mDKO model, these mice do not exhibit premature mortality, thereby providing an ideal system for longitudinal studies on aged animals. Specifically, this thesis focuses on evaluating how the absence of muscle-specific IL-6 in aged mice modulates cellular senescence and skeletal muscle homeostasis. Our data indicate that while IL-6 deficiency in old mice mitigates aging in peripheral tissues like the liver, it negatively impacts skeletal muscle by inducing atrophy.