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Abstract
BackgroundThe regulation of muscle stem cells in humans in response to muscle injury remains largely undefined. Recently, interleukin-6 (IL-6) has been implicated in muscle stem cell (satellite cell)-mediated muscle hypertrophy in animals; however, the role of IL-6 in the satellite cell (SC) response following muscle-lengthening contractions in humans has not been studied.Methodology/Principal FindingsEight subjects (age 22±1 y; 79±8 kg) performed 300 maximal unilateral lengthening contractions (3.14 rad.s−1) of the knee extensors. Blood and muscle samples were collected before and at 4, 24, 72, and 120 hours post intervention. IL-6, IL-6 receptor (IL-6Rα), cyclin D1, suppressor of cytokine signling-3 (SOCS3) mRNA were measured using quantitative RT-PCR and serum IL-6 protein was measured using an ELISA kit. JAK2 and STAT3 phosphorylated and total protein was measured using western blotting techniques. Immunohistochemical analysis of muscle cross-sections was performed for the quantification of SCs (Pax7+ cells) as well as the expression of phosphorylated STAT3, IL-6, IL-6Rα, and PCNA across all time-points. The SC response, as defined by an amplification of Pax7+ cells, was rapid, increasing by 24 h and peaking 72 h following the intervention. Muscle IL-6 mRNA increased following the intervention, which correlated strongly (R2 = 0.89, p<0.002) with an increase in serum IL-6 concentration. SC IL-6Rα protein was expressed on the fiber, but was also localized to the SC, and IL-6+ SC increased rapidly following muscle-lengthening contractions and returned to basal levels by 72 h post-intervention, demonstrating an acute temporal expression of IL-6 with SC. Phosphorylated STAT3 was evident in SCs 4 h after lengthening contraction, and the downstream genes, cyclin D1 and SOCS3 were significantly elevated 24 hours after the intervention.Conclusions/SignificanceThe increased expression of STAT3 responsive genes and expression of IL-6 within SCs demonstrate that IL-6/STAT3 signaling occurred in SCs, correlating with an increase in SC proliferation, evidenced by increased Pax7+/PCNA+ cell number in the early stages of the time-course. Collectively, these data illustrate that IL-6 is an important signaling molecule associated with the SC response to acute muscle-lengthening contractions in humans.
Highlights
Muscle specific stem cells, named satellite cells (SCs), are necessary for muscle repair and regeneration and are known to reside in skeletal muscle between the basal lamina and the sarcolemma
IL6Ra gene expression was significantly increased in whole muscle at T4 (p,0.001); these changes were transient as expression levels returned to pre-intervention biopsy (PRE) values by T24 (Fig. 1d)
It has been recently shown that primary myoblasts isolated from mice possess the IL-6Ra, it remains unknown whether human satellite cells possess the IL-6Ra [17]
Summary
Muscle specific stem cells, named satellite cells (SCs), are necessary for muscle repair and regeneration and are known to reside in skeletal muscle between the basal lamina and the sarcolemma. The contribution of new myonuclei to muscle fibers, from SCs, is necessary to promote postnatal muscle growth and to prevent the loss of functional capacity and increased morbidity and mortality associated with muscle loss in advanced age and disease (bedrest, cachexia, etc.) [3,4,5]. The contribution of many of these potential SC regulators to hypertrophy and muscle repair, in vivo, is not known. The regulation of muscle stem cells in humans in response to muscle injury remains largely undefined. Interleukin-6 (IL-6) has been implicated in muscle stem cell (satellite cell)-mediated muscle hypertrophy in animals; the role of IL-6 in the satellite cell (SC) response following muscle-lengthening contractions in humans has not been studied
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