Muscle cell-derived cytokines in skeletal muscle regeneration.

Regeneration of the mammalian adult skeletal muscle is a well-orchestrated process regulated by multiple proteins and signalling pathways. Cytokines constitute a major class of regulators of skeletal myogenesis. It is well established that infiltrating immune cells at the site of muscle injury secrete cytokines, which play critical roles in the myofibre repair and regeneration process. In the past 10-15 years, skeletal muscle itself has emerged as a prolific producer of cytokines. Much attention in the field has been focused on the endocrine effects of muscle-secreted cytokines (myokines) on metabolic regulation. However, ample evidence suggests that muscle-derived cytokines also regulate myogenic differentiation and muscle regeneration in an autocrine manner. In this review, we survey cytokines that meet two criteria: (a) evidence of expression by muscle cells; (b) evidence demonstrating a myogenic function. Dozens of cytokines representing several major classes make up this group, and together they regulate all steps of the myogenic process. How such a large array of cytokines coordinate their signalling to form a regulatory network is a fascinating, pressing question. Functional studies that can distinguish the source of the cytokines in vivo are also much needed in order to facilitate exploration of their full therapeutic potential.

Muscle-derived TRAIL negatively regulates myogenic differentiation.

TNF-related apoptosis-inducing ligand (TRAIL) is known to induce apoptosis in cancer cells, although non-apoptotic functions have also been reported for this cytokine in various cell types. TRAIL and its receptor TRAIL-R2 are expressed in skeletal muscles, but a potential role of muscle-derived TRAIL in myogenesis has not been explored. Here we report that TRAIL is an autocrine regulator of myogenic differentiation. Knockdown of TRAIL or TRAIL-R2 enhanced C2C12 myoblast differentiation, and recombinant TRAIL inhibited expression of the cell cycle inhibitor p21, accompanied by suppression of myoblasts from exiting the cell cycle, a requisite step in the myogenic differentiation process. Blocking cell cycle progression restored differentiation from inhibition by recombinant TRAIL, supporting the notion that TRAIL exerts its effect in myogenesis through modulating cell cycle exit. We also found that TRAIL knockdown led to enhanced muscle regeneration in mice upon injury, recapitulating the in vitro observation. Additionally, inhibition of ERK activation reversed the negative effect of recombinant TRAIL on p21 expression and myoblast differentiation, suggesting that ERK signaling may be a mediator of TRAIL's function to suppress cell cycle withdrawal and inhibit differentiation. Taken together, our findings uncover a muscle cell-autonomous non-apoptotic function of TRAIL in skeletal myogenesis.

Cxcl14 depletion accelerates skeletal myogenesis by promoting cell cycle withdrawal.

Skeletal muscle in adults retains a robust ability to regenerate after injury, which progressively declines with age. Many of the regulators of skeletal myogenesis are unknown or incompletely understood. Intriguingly, muscle cells secrete a wide variety of factors, such as cytokines, which can influence muscle development and regeneration in an autocrine or paracrine manner. Here we describe chemokine (C-X-C motif) ligand 14 (Cxcl14) as a novel negative regulator of skeletal myogenesis. We found that Cxcl14 expression in myoblasts prevented cell cycle withdrawal, thereby inhibiting subsequent differentiation. Knockdown of Cxcl14 in vitro enhanced myogenic differentiation through promoting cell cycle withdrawal in an ERK1/2-dependent manner. Recapitulating these in vitro observations, the process of muscle regeneration following injury in young adult mice was accelerated by Cxcl14 depletion, accompanied by reduced cell proliferation. Furthermore, impaired capacity for muscle regeneration in aging mice was fully restored by Cxcl14 depletion. Our results indicate that Cxcl14 may be a promising target for development of therapeutics to treat muscle disease, especially aging-related muscle wasting.

A Tale of Two Cysts: Steatocystoma Multiplex and Eruptive Vellus Hair Cysts-Two Case Reports and a Review of the Literature.

Background. Steatocystoma multiplex (SM) and eruptive vellus hair cysts (EVHC) are uncommon benign tumors of the pilosebaceous unit. Both SM and EVHC are characterized by smooth, asymptomatic papules or nodules, most commonly presenting on the chest, limbs, and abdomen. Most cases of SM and EVHC are sporadic, although less common autosomal dominant inherited forms have been reported. Main Observation. In this report we present two cases of cutaneous cysts exhibiting characteristics of either SM or EVHC. Both patients presented with numerous 1-2 mm asymptomatic papules and responded well to surgical expression by incision and drainage (I&D). Conclusion. SM and EVHC are similar in clinical presentation and management. Previously reported "hybrid-type" tumors present strong evidence for a relationship between the two lesions pathologically. Due to potential similarity of EVHC and SM cyst contents, I&D and subsequent microscopic examination cannot definitely differentiate between EVHC, SM, and hybrid cysts.