Endocrinol Metab.  2022 Jun;37(3):408-414. 10.3803/EnM.2022.302.

Human Tissue-Engineered Skeletal Muscle: A Tool for Metabolic Research

• Kim JH
• Yu SM
• Son JW

• KMID: 2531384
• DOI: http://doi.org/10.3803/EnM.2022.302

Abstract

Skeletal muscle is now regarded as an endocrine organ based on its secretion of myokines and exerkines, which, in response to metabolic stimuli, regulate the crosstalk between the skeletal muscle and other metabolic organs in terms of systemic energy homeostasis. This conceptual basis of skeletal muscle as a metabolically active organ has provided insights into the potential role of physical inactivity and conditions altering muscle quality and quantity in the development of multiple metabolic disorders, including insulin resistance, obesity, and diabetes. Therefore, it is important to understand human muscle physiology more deeply in relation to the pathophysiology of metabolic diseases. Since monolayer cell lines or animal models used in conventional research differ from the pathophysiological features of the human body, there is increasing need for more physiologically relevant in vitro models of human skeletal muscle. Here, we introduce recent studies on in vitro models of human skeletal muscle generated from adult myogenic progenitors or pluripotent stem cells and summarize recent progress in the development of three-dimensional (3D) bioartificial muscle, which mimics the physiological complexity of native skeletal muscle tissue in terms of maturation and functionality. We then discuss the future of skeletal muscle 3D-organoid culture technology in the field of metabolic research for studying pathological mechanisms and developing personalized therapeutic strategies.

Keyword

Metabolic diseases; Muscle, skeletal; Stem cells; Pluripotent stem cells; Cell culture techniques, three dimensional

Figure

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  Fig. 1. Recreation of human skeletal muscle in vitro. Human skeletal muscle can be established in vitro using induced pluripotent stem cells (iPSCs) and adult muscle stem cells (MuSCs). iPSCs are differentiated by the exogenous expression of transcriptional regulators or by using a combination of growth factors and signaling molecules. The resulting myoblasts may be encapsulated in support substrates such as hydrogels and formed into myotubes, then arranged into three-dimensional (3D) myofibers mimicking the skeletal muscle tissue. iPSC-derived neural and endothelial cells may be included along with supporting cells to form more complex models that better recapitulate the microenvironment of native skeletal muscles. 3D bioprinting and scaffold-based culture methods may be used for improved replication of native muscle tissue structure, and muscle innervation may be simulated to test the function and performance of the constructed skeletal muscle. BMP, bone morphogenic protein; Shh, sonic hedgehog protein; Pax7, paired box 7; MyoD, myoblast determination protein; Myf5, myogenic factor 5; PSC, pluripotent stem cell; Cxcl4, CXC chemokine ligand 4; 2D, three-dimensional.

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  Fig. 2. Potential applications of three-dimensional human skeletal muscle. The skeletal muscle is a major regulator of energy metabolism that communicates with multiple organ systems and is one of the major organs affected by metabolic syndrome. Devices such as multi-organ on a chip can be used to replicate the inter-organ communication between the skeletal muscle and other organs such as the liver, serving as a platform to comprehensively model these communication networks. Furthermore, recent advances in genetic engineering technology and cell reprogramming using patient-derived pluripotent stem cells (PSCs) have made it possible to generate disease models of metabolic syndrome, facilitating the path toward precision medicine.

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