Elevated SOCS3 and altered IL-6 signaling is associated with age-related human muscle stem cell dysfunction

Aging is associated with increased circulating interleukin-6 (IL-6) and a reduced myogenic capacity, marked by reduced muscle stem cell [satellite cell (SC)] activity. Although IL-6 is important for normal SC function, it is unclear whether elevated IL-6 associated with aging alters SC function. We hypothesized that mild chronically elevated IL-6 would be associated with a blunted SC response through altered IL-6 signaling and elevated suppressor of cytokine signaling-3 (SOCS3) in the elderly. Nine healthy older adult men (OA; 69.6 ± 3.9 yr) and 9 young male controls (YC; 21. 3 ± 3.1 yr) completed 4 sets of 10 repetitions of unilateral leg press and knee extension (75% of 1-RM). Muscle biopsies and blood were obtained before and 3, 24, and 48 h after exercise. Basal SC number was 33% lower in OA vs. YC, and the response was blunted in OA. IL-6(+)/Pax7(+) cells demonstrated a divergent response in OA, with YC increasing to 69% at 3 h and peaking at 24 h (72%), while IL-6(+)/Pax7(+) cells were not increased until 48 h in OA (61%). Type II fiber-associated phosphorylated signal transducer and activator of transcription (pSTAT3)(+)/Pax7(+) cells demonstrated a similar delay in OA, not increasing until 48 h (vs. 3 h in YC). SOCS3 protein was 86% higher in OA. These data demonstrate an age-related impairment in normal SC function that appears to be influenced by SOCS3 protein and delayed induction of IL-6 and pSTAT3 in the SCs of OA. Collectively, these data suggest dysregulated IL-6 signaling as a consequence of aging contributes to the blunted muscle stem cell response.