Person:

Hirshman, Michael

Parabiosis experiments indicate that impaired regeneration in aged mice is reversible by exposure to a young circulation, suggesting that young blood contains humoral “rejuvenating” factors that can restore regenerative function. Here, we demonstrate that the circulating protein growth differentiation factor 11 (GDF11) is a rejuvenating factor for skeletal muscle. Supplementation of systemic GDF11 levels, which normally decline with age, by heterochronic parabiosis or systemic delivery of recombinant protein, reversed functional impairments and restored genomic integrity in aged muscle stem cells (satellite cells). Increased GDF11 levels in aged mice also improved muscle structural and functional features and increased strength and endurance exercise capacity. These data indicate that GDF11 systemically regulates muscle aging and may be therapeutically useful for reversing age-related skeletal muscle and stem cell dysfunction.

Mice deficient in c-jun-NH2-terminal kinase 1 (JNK1) exhibit decreased fasting blood glucose and insulin levels, and protection against obesity-induced insulin resistance, suggesting increased glucose disposal into skeletal muscle. Thus, we assessed whether JNK1 deficiency enhances muscle glucose metabolism. Ex vivo insulin or contraction-induced muscle [H-3]2-deoxyglucose uptake was not altered in JNK1 knockout mice, demonstrating that JNK1 does not regulate blood glucose levels via direct alterations in muscle. In vivo muscle [3H]2-deoxyglucose uptake in response to a glucose injection was also not enhanced by JNK1 deficiency, demonstrating that a circulating factor was not required to observe altered muscle glucose uptake in the knockout mice. JNK1 deficiency did not affect muscle glycogen levels or the protein expression of key molecules involved in glucose metabolism. This study is the first to directly demonstrate that enhanced skeletal muscle glucose metabolism does not underlie the beneficial effects of JNK1 deficiency in lean mice.