Striated muscle function, regeneration, and repair

Abstract

As the only striated muscle tissues in the body, skeletal and cardiac muscle share numerous structural and functional characteristics, while exhibiting vastly different size and regenerative potential. Healthy skeletal muscle harbors a robust regenerative response that becomes inadequate after large muscle loss or in degenerative pathologies and aging. In contrast, the mammalian heart loses its regenerative capacity shortly after birth, leaving it susceptible to permanent damage by acute injury or chronic disease. In this review, we compare and contrast the physiology and regenerative potential of native skeletal and cardiac muscles, mechanisms underlying striated muscle dysfunction, and bioengineering strategies to treat muscle disorders. We focus on different sources for cellular therapy, biomaterials to augment the endogenous regenerative response, and progress in engineering and application of mature striated muscle tissues in vitro and in vivo. Finally, we discuss the challenges and perspectives in translating muscle bioengineering strategies to clinical practice.

Keywords: Cardiac; Muscle; Skeletal; Stem cells; Tissue engineering; iPS.

Fig. 1

Structure and function of striated muscles. a Adult skeletal muscle contains uniformly aligned, long multinucleated myofibers, blood vessels, and resident satellite cells, with fewer fibroblasts relative to cardiac muscle. b Adult cardiac muscle consists of a branched network of shorter cardiomyocytes connected via intercalated discs and surrounded by blood vessels and extracellular matrix secreted primarily by fibroblasts. c Skeletal muscle excitation–contraction (e–c) coupling begins with a depolarization-induced conformational change in l-type Ca²⁺ channels (Ca_V1.1, dihydropyridine receptor, DHPR) that triggers release of Ca²⁺ from two neighboring SR terminae via opening of the Ryanodine receptor (RyR1) channels, creating a triad (rather than a diad as in cardiac muscle) with the T-tubules. Calcium is pumped back into the SR via the SR-ATP-ase (SERCA1a). d Cardiac E-C coupling occurs through a Ca²⁺-dependent Ca²⁺ release wherein T-tubular entry of extracellular Ca²⁺ through depolarization activated L-type Ca²⁺ channels (Ca_V1.2) triggers a release of Ca²⁺ stored in the sarcoplasmic reticulum (SR) via opening of the RyR2 channels. Calcium is pumped back into the SR via the SR-ATP-ase (SERCA2a). e Tetanic responses of slow and fast-twitch skeletal muscle fibers showing increased ability to recover from fast-paced stimulation in fast-twitch fibers. f Comparison of active and passive tension-length relationships in cardiac and skeletal muscle. Both striated muscles exhibit stronger active (contractile) force with increased muscle length followed by decay at higher levels of stretch (Frank-Starling relationship). While skeletal muscle operates close to the peak of its active force–length curve, cardiac muscle operates at the ascending limb of the curve to allow more forceful contraction at larger diastolic filling. Simultaneously, passive tension of cardiac muscle at its operating length is markedly higher than that of skeletal muscle, primarily due to higher stiffness of titin molecules within the sarcomeres. g Unlike skeletal muscle, cardiac muscle can propagate action potentials (APs) between myocytes that are connected via gap junctions. Schematic depicts an isochrone map showing AP propagation through cardiac muscle, from which conduction velocity can be measured. h Positive force-frequency relationship of cardiac muscle demonstrating increased force production at higher excitation rates

Fig. 2

Endogenous and exogenous repair of striated muscles. a Damage to skeletal muscle results in proliferation and migration of satellite cells (SCs) along the longitudinal axis of dying fibers (gray) and initial infiltration of pro-inflammatory M1-macrophages and neutrophils which aids in the degeneration of damaged fibers. Conversion to and infiltration of M2-macrophages stimulates SCs to differentiate and eventually fuse into functional myofibers. b Ischemic injury to cardiac muscle results in death of cardiomyocytes (CMs), an initial infiltration of neutrophils and upregulation of matrix metalloproteinases. Release of TGF-β from necrotic CMs induces late migration of macrophages and fibroblasts as well as transformation of fibroblasts into myofibroblasts, which secrete collagen to ultimately produce a fibrotic scar. c Striated muscle repair can be augmented via exogenous delivery of single cells, biomaterials with or without cells, as well as transplantation of in vitro engineered functional muscle tissues