Interleukin-6 (IL-6) is a pleiotropic cytokine able to exert pro-regenerative effects in muscle tissue and to induce catabolic/pro-inflammatory pathways, depending on the levels, the time of action and the activated signaling. Locally and transiently produced IL-6 positively influence muscle tissue, being required for satellite cell proliferation. Otherwise, persistent and sustained levels of circulating IL-6 have been reported to induce muscle atrophy and wasting.
Increased levels of serum IL-6 have been found under several physio-pathologic conditions, including aging, cancer cachexia and muscular dystrophies. Duchenne muscular dystrophy is a genetic disease characterized by a progressive degeneration of myofibers. Downstream the genetic defect, secondary mechanisms, as chronic inflammation and excessive ROS production, contribute to the progression of pathology. We demonstrated that elevated levels of circulating IL-6 exacerbates the dystrophic phenotype of mdx mice, more closely approximating human pathology. A key role of IL-6 in perturbing the redox-balance of dystrophic muscles has been also elucidated by our studies. Data from our group also highlighted an attenuated muscle pathology in mdx mice in which a short-term inhibition of IL-6 trans-signaling has been performed.
Basing on these evidences the main goal of the proposed project is to better clarify the impact of the stimulation/inhibition of IL-6 signaling on muscle homeostasis. To this aim I will use a mouse model in which IL-6 is overexpressed in a non-pathologic background, to evaluate the direct contribute of IL-6 in promoting mechanisms involved in the perturbation of skeletal muscle homeostasis, as the alteration of the redox-signaling cascade. Moreover, I will analyse a newly generated dystrophic model, knocked out for the expression of the IL-6 receptor alpha, to evaluate whether long-lasting interference with IL-6 signaling can ameliorate secondary symptoms of the disease.
Skeletal muscle represents one of the most abundant and important tissues in vertebrates. Along with functional and structural properties, muscle metabolism exerts a great influence on the general metabolic balance, influencing the behavior of several other organs and tissues within the entire body. Indeed, muscle not only is a target of mediators such as hormones but it has been recognized as an endocrine organ able to produce and secrete factors (myokines) with autocrine, paracrine and endocrine function. Alterations in skeletal muscle tissue can thus have an impact on the general physiology of the organism. The loss of functional muscle tissue occurs under several pathologic and physiologic conditions including aging, immobilization, denervation and muscular dystrophies (Forcina et al. 2018). The incidence of muscle atrophy and wasting represents a clinical condition impinging the quality of life during aging and contributing to the disease progression in pathology.
The progressive reduction myofibers size and number have an impact on muscle functionality and has been linked to different stressors, including inflammation, metabolic stress and altered muscle redox balance (Mitchell and Pavlath 2001; Powers, Smuder, and Judge 2012). However, molecular mechanisms underlining muscle atrophy and wasting are not fully elucidate. Thus, a better characterization of pathways and factors affecting skeletal muscle homeostasis might be required to investigate potential therapeutic approaches. The innovative aspect of this project is related to the possibility to disclose the role of IL-6 in muscle homeostasis by using different animal models. Taking the advantage of the NSE/IL-6 mouse model, over-expressing IL-6 is serum since early after birth, I will better clarify the impact of high levels of circulating IL-6 on healthy skeletal muscle. Moreover, using this specific model I can investigate the possible direct contribute of IL-6 in enhancing ROS production and perturbing the redox balance in muscle tissue, aside from muscle pathology.
The negative role of IL-6 in the field of muscle pathology (i.e. Duchenne muscular dystrophy) has been intensely studied. Our recent works evidenced how the over-expression of IL-6 in dystrophic mice (mdx/IL-6 mouse model) induced the exacerbation of the dystrophic phenotype enhancing muscle necrosis, inflammation and ROS production, also affecting the maintenance of the muscle stem cell pool and the endogenous anti-oxidant response (Pelosi et al. 2015b; Petrillo et al. 2017; Pelosi et al., 2017). In addition, data from our group highlighted how the pharmacologic interference with IL-6 trans-signaling reduced muscle necrosis and attenuated the inflammatory response in mdx muscle (Pelosi at al. 2015a). Basing on the results, obtained with the short-term treatment with a pharmacologic inhibitor of IL6R, we generated a novel transgenic mouse constitutively knocked out for the IL-6 receptor alpha, to evaluate the effect of a prolonged inhibition of the IL-6 signaling pathway in mdx mice. This newly generated animal model could allow the improvement of knowledge about the involvement of IL-6 trans-signaling in pathogenic mechanisms inducing muscle wasting in DMD. Increasing evidences regarding the interference with IL-6 pathway might contribute to the development of potential treatments to counteract the loss of functional tissue in muscle pathology.