Exercise mimetics and JAK inhibition attenuate IFN-γ–induced wasting in engineered human skeletal muscle

Abstract

Chronic inflammatory diseases often lead to muscle wasting and contractile deficit. While exercise can have anti-inflammatory effects, the underlying mechanisms remain unclear. Here, we used an in vitro tissue-engineered model of human skeletal muscle (“myobundle”) to study effects of exercise-mimetic electrical stimulation (E-stim) on interferon-γ (IFN-γ)–induced muscle weakness. Chronic IFN-γ treatment of myobundles derived from multiple donors induced myofiber atrophy and contractile loss. E-stim altered the myobundle secretome, induced myofiber hypertrophy, and attenuated the IFN-γ–induced myobundle wasting and weakness, in part by down-regulating JAK (Janus kinase)/STAT1 (signal transducer and activator of transcription 1) signaling pathway amplified by IFN-γ. JAK/STAT inhibitors fully prevented IFN-γ–induced myopathy, confirming the critical roles of STAT1 activation in proinflammatory action of IFN-γ. Our results reveal a previously unknown mechanism of the cell-autonomous anti-inflammatory effects of muscle exercise and establish the utility of human myobundle platform for studies of inflammatory muscle disease and therapy.

Recent Trends in Biofabrication Technologies for Studying Skeletal Muscle Tissue-Related Diseases

“…In particular, inhibited expression of IFN-γ-induced JAK (Janus kinase)/STAT (signal transducer and activator of transcription) pathway downstream proteins suggested the previously unknown, exercise-mediated cell autonomous anti-inflammatory response that occurs in the muscle tissue, besides the paracrine signalling which has been traditionally suggested as the fundamental mechanism. Furthermore, prevention of muscle atrophy after treatment of FDA-approved smallmolecule inhibitors of JAK/STAT pathway confirmed the utility of this platform for preclinical drug screening (Chen et al, 2021). Juhas et al (2018) established a 3D co-culture system based on previously referred 3D engineered muscle to assess the role of macrophages in skeletal muscle regeneration process.…”

“…Electrical stimulation prevented IFN-γ-induced decrease of sarcomere organization. Reprinted with permission from ( Chen et al, 2021 ).…”

Compressive Buckling Fabrication of 3D Cell‐Laden Microstructures

“…The hierarchical 3D tissue architecture is important to tissue's biological functions. [ 26 , 27 , 28 , 29 ] Recreating the native tissue structure in engineered tissue is a challenging task and a variety of approaches such as microfabrication and 3D printing have been developed in the past decades. [ 6 , 30 , 31 , 32 , 33 ] 3D bioprinting is an emerging technology that allows spatially‐controlled deposition of cells and ECMs and has been used to build engineered tissues representing bone, [ 34 ] vasculature, [ 16 , 35 ] liver, [ 36 ] and cartilage.…”

Spotlight on Three Rs Progress

“…A system has been developed in order to shed light on the anti-inflammatory effects of exercise on muscle cells in vitro . The article by Chen et al 1 described how the team generated ‘myobundles’ from donated human skeletal muscle, which were subjected to IFN-γ treatment to reproduce the muscle atrophy and contractile deficit often seen in chronic inflammatory diseases. This strategy ensured that any effects observed were not due to other cell types.…”