Tackling muscle fibrosis: From molecular mechanisms to next generation engineered models to predict drug delivery

Abstract

Muscle fibrosis represents the end stage consequence of different diseases, among which muscular dystrophies, leading to severe impairment of muscle functions. Muscle fibrosis involves the production of several growth factors, cytokines and proteolytic enzymes and is strictly associated to inflammatory processes. Moreover, fibrosis causes profound changes in tissue properties, including increased stiffness and density, lower pH and oxygenation. Up to now, there is no therapeutic approach able to counteract the fibrotic process and treatments directed against muscle pathologies are severely impaired by the harsh conditions of the fibrotic environment. The design of new therapeutics thus need innovative tools mimicking the obstacles posed by the fibrotic environment to their delivery. This review will critically discuss the role of in vivo and 3D in vitro models in this context and the characteristics that an ideal model should possess to help the translation from bench to bedside of new candidate anti-fibrotic agents.

Rheumatoid cachexia: the underappreciated role of myoblast, macrophage and fibroblast interplay in the skeletal muscle niche

“…4. M1 macrophages release TNF-α and IL-6 which stimulate the proliferation of fibroblasts and FAPs [85], but upon binding to excess fibrinogen also increase the production of IL-1β and TGF-β [86]. TNF-α and IL-1β increase the synthesis of collagenases contributing to the destruction of the cartilage in RA [45,53,56].…”

“…This profibrotic growth factor is present in skeletal muscle following injury and in dystrophic muscle, where it stimulates fibroblasts to produce ECM components [79,88]. During regeneration, the degradation of the initial scaffold of ECM contributes to the generation of protein fragments that mediate biological activities involved in normal tissue repair [73,79,85]. However, TGFβ reduces the production of enzymes (such as collagenase) and stimulates the production of tissue inhibitors of metalloproteinases (TIMPs) and plasminogen activator inhibitor type-1 (PAI-1), thereby inhibiting the degradation of the ECM [83,88] and disturbing the final outcome.…”

Phagocytosis mediated by scavenger receptor class BI promotes macrophage transition during skeletal muscle regeneration

“…Thus, we speculate that the source of TGF␤ expressing in skeletal muscle after injury may be multiple. In fact, TGF␤ can be produced by different types of cells, including inflammatory cells, mesenchymal cells, and epithelial cells (39). In skeletal muscle, impaired muscle regeneration is often accompanied by more severe interstitial fibrosis.…”

Engineering an Environment for the Study of Fibrosis: A 3D Human Muscle Model with Endothelium Specificity and Endomysium

“…The behavior of fibroblasts in skeletal muscles is known to play a key role in muscle-wasting disorders, particularly in the replacement of functional muscle cells with ECM-based, noncontractile connective tissue (Grounds, 2008;Zanotti et al, 2016). Conventional 2D assays are generally limited to the study of the intracellular levels of specific proteins (Stahnke et al, 2017), since the lack of 3D architectural arrangement does not allow the quantification of the 3D accumulation and the distribution of proteins in the surrounding environment (Bersini et al, 2018). In this framework, the lack of a physiological 3D matrix in which secreted proteins can gradually accumulate could reduce the differences between experimental groups.…”