Electrical stimulation of biofidelic engineered muscle enhances myotube size, force, fatigue resistance, and induces a fast-to-slow-phenotype shift

Abstract

Ther­a­peu­tic devel­op­ment for skele­tal mus­cle dis­eases is chal­lenged by a lack of ex vivo mod­els that reca­pit­u­late human mus­cle phys­i­ol­o­gy. Here, we engi­neered 3D human skele­tal mus­cle tis­sue in the Biowire II plat­form that could be main­tained and elec­tri­cal­ly stim­u­lat­ed long-term. Increas­ing dif­fer­en­ti­a­tion time enhanced myotube for­ma­tion, mod­u­lat­ed myo­genic gene expres­sion, and increased twitch and tetan­ic forces. When we mim­ic­ked exer­cise train­ing by apply­ing chron­ic elec­tri­cal stim­u­la­tion, the ​“exer­cised” skele­tal mus­cle tis­sues showed increased myotube size and a con­trac­til­i­ty pro­file, fatigue resis­tance, and gene expres­sion changes com­pa­ra­ble to in vivo mod­els of exer­cise train­ing. Addi­tion­al­ly, tis­sues also respond­ed with expect­ed phys­i­o­log­i­cal changes to known phar­ma­co­log­i­cal treat­ment. To our knowl­edge, this is the first evi­dence of a human engi­neered 3D skele­tal mus­cle tis­sue that reca­pit­u­lates in vivo mod­els of exer­cise. By reca­pit­u­lat­ing key fea­tures of human skele­tal mus­cle, we demon­strat­ed that the Biowire II plat­form may be used by the phar­ma­ceu­ti­cal indus­try as a mod­el for iden­ti­fy­ing and opti­miz­ing ther­a­peu­tic drug can­di­dates that mod­u­late skele­tal mus­cle function.