Restoring Systemic GDF11 Levels Reverses Age-Related Dysfunction in Mouse Skeletal Muscle

Abstract

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.

Lifelong exercise, but not short-term high-intensity interval training, increases GDF11, a marker of successful aging: a preliminary investigation

“…Moreover, treatment with recombinant GDF11 returned grip strength to near young levels, and improved running endurance performance (Sinha et al. 2014). However, it has also been noted that GDF11 may inhibit myoblast differentiation into mature myotubes in a myostatin‐like manner (Egerman et al.…”

“…Similarly, the aging muscle phenotype is partially offset by provision of recombinant GDF11, as demonstrated by increased grip strength and running endurance in mice (Sinha et al. 2014). …”

Lack of evidence for GDF 11 as a rejuvenator of aged skeletal muscle satellite cells

“…GDF11 was recently proposed to decline in concentration in old mice and to restore young tissue function phenotypes in the heart, CNS, and skeletal muscle (Loffredo et al ., 2013; Sinha et al ., 2014). It was proposed that GDF11 promotes skeletal muscle regeneration by restoring genomic integrity of old skeletal muscle satellite cells (SCs) and thereby promoting their outgrowth in response to injury (Sinha et al ., 2014).…”

“…GDF11 was recently proposed to decline in concentration in old mice and to restore young tissue function phenotypes in the heart, CNS, and skeletal muscle (Loffredo et al ., 2013; Sinha et al ., 2014). It was proposed that GDF11 promotes skeletal muscle regeneration by restoring genomic integrity of old skeletal muscle satellite cells (SCs) and thereby promoting their outgrowth in response to injury (Sinha et al ., 2014). To identify factors that may regulate the growth with aging, we screened a comprehensive expression library of extracellular proteins (Zhang et al ., 2014) on aged skeletal muscle SCs (additional screen details to be published elsewhere).…”

“…rGDF8 reduced young SC numbers (Fig. 1B, P  <   0.05) consistent with published findings (Sinha et al ., 2014; Egerman et al ., 2015). However, we observed rGDF11 also tended to reduce young SC numbers ( P  < 0.05) in agreement with Egerman et al .…”