Tissue-Engineered Skeletal Muscle Models to Study Muscle Function, Plasticity, and Disease

Abstract

Skeletal muscle possesses remarkable plasticity that permits functional adaptations to a wide range of signals such as motor input, exercise, and disease. Small animal models have been pivotal in elucidating the molecular mechanisms regulating skeletal muscle adaptation and plasticity. However, these small animal models fail to accurately model human muscle disease resulting in poor clinical success of therapies. Here, we review the potential of in vitro three-dimensional tissue-engineered skeletal muscle models to study muscle function, plasticity, and disease. First, we discuss the generation and function of in vitro skeletal muscle models. We then discuss the genetic, neural, and hormonal factors regulating skeletal muscle fiber-type in vivo and the ability of current in vitro models to study muscle fiber-type regulation. We also evaluate the potential of these systems to be utilized in a patient-specific manner to accurately model and gain novel insights into diseases such as Duchenne muscular dystrophy (DMD) and volumetric muscle loss. We conclude with a discussion on future developments required for tissue-engineered skeletal muscle models to become more mature, biomimetic, and widely utilized for studying muscle physiology, disease, and clinical use.

Contractile force assessment methods for in vitro skeletal muscle tissues

“…Electrical stimulation causes depolarization of the muscle cell membrane, which triggers excitation-contraction coupling ( Merrill et al, 2005 ; Uchimura et al, 2021 ). It is essential to optimize the electrical parameters for each experimental setup and culture stage, since inadequate stimulation can result in culture damage or untoward responses, including fatigue, electrochemical damage, or electroporation effect, leading to increased membrane permeability and impaired cell function ( Nikolić et al, 2017 ; Khodabukus and Baar, 2012 ; Mills et al, 2019 ; Ruzgys et al, 2019 ; Nagamine et al, 2011 ; Khodabukus, 2021 ).…”

“…Despite the many discoveries regarding those models, a comparison with native human muscle suggests that major challenges remain in order to obtain a fully representative or trustworthy model ( Horvath et al, 2016 ; Santoso et al, 2021 ; Wang et al, 2019 ). Characteristics such as size, drug diffusion, or immune response are difficult to match with the ones occurring in the human body ( Fernández-Costa et al, 2021 ; Khodabukus, 2021 ). For instance, the muscular dystrophy X-linked mouse (mdx) is a well-accepted preclinical model for Duchenne Muscular Dystrophy (DMD) ( Bersini et al, 2018 ; Lasa-Fernandez et al, 2020 ; Al Tanoury et al, 2021 ).…”

Neuromuscular Development and Disease: Learning From in vitro and in vivo Models

“…A subset of these Pax7+ progenitors localize under the basal lamina where the eventually become satellite cells which contribute to the repair and regeneration of damaged muscle fibers in adults ( Dumont et al, 2015a ). During muscle fiber maturation, expression of embryonic myosin heavy chain changes to adult myosin heavy chain isoforms with oxidative, slow twitch or glycolytic, fast twitch fiber phenotypes ( Khodabukus, 2021 ). Additionally, actin and myosin assemble into sarcomeres, sarcomeres assemble into myofibrils, NMJs are formed at the sarcolemma, and triads are established from a network of tubules for facilitated neural excitation ( Pourquié et al, 2018 ).…”

Muscular Plasticity In Terms Of Exercise Physiology

“…Egzersiz Fizyolojisi Bağlamında Musküler Plastisite. Gaziantep Üniversitesi Spor Bilimleri Dergisi, 6(3), 266-278. 274 iskelet kası hipertrofisiyle mTORC1 (mammalian target of rapamycin complex 1) aktivasyonunun bağlantısı bulunmaktadır (Khodabukus, 2021). Diet ile ilgili araştırmalar, zeytinyağında bulunan oleik asit ve asit, mısır yağı gibi maddelerin içerisinde bulunan linoleik asitin vasküler düz kas üzerinde proliferatif etkilere neden olduğunu, kas büyümesini düzenleyebileceğini ve kas diferansiyasyonu sırasındaki total fosfolipid içeriğini arttığını göstermiştir (Kelley ve ark., 2006).…”