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Try out PMC Labs and tell us what you think. Learn More. 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 Dq on the muscular adult dating river 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. The body possesses two types of striated muscle, cardiac and skeletal. Striated muscles are required for whole-body oxygen supply, metabolic balance, and locomotion. While structurally and functionally similar, the two striated muscles have vastly different sizes and regenerative capacities. Skeletal muscle can regenerate in response to small muscle tears that occur during exercise or daily activity owing to the abundances of resident muscle stem cells called satellite cells SCswhich upon injury activate, proliferate, and fuse to repair damaged or form new muscle fibers [ 4 ].
In contrast, cardiac muscle does not possess a cardiomyogenic stem cell pool and has little to no regenerative ability, with injury resulting in the formation of a fibrotic scar and, eventually, impaired pump function [ 5 ]. Functional deficit in skeletal muscle occurs with age, chronic degenerative diseases such as muscular dystrophy [ 6 ], defects in metabolism such as Pompe disease [ 7 ], and with large volume muscle loss due to trauma or surgical resection [ 8 ]. In these conditions, SC pool is often depleted due to the disruption of SC niche or continuous SC activation resulting in impaired muscle regeneration and chronic fibrosis [ 9 ].
Cardiac muscle dysfunction arises largely from narrowing of coronary arteries caused by vascular disease and less frequently from non-ischemic cardiomyopathy, congenital abnormalities, diastolic disease, and certain muscular dystrophies [ 1011 ].
In this review, we first discuss the structure, function, and regenerative potential of healthy striated muscles, representing the desired outcome of any cell, biomaterial, drug, or gene therapy for muscle disorders. We then review the progress made with cellular therapies, where immature cells are directly delivered in vivoas well as cell-free therapies where biomaterials are implanted to augment and replicate the natural repair capacity of muscle tissue.
Lastly, we review recent developments in engineering mature striated muscle tissues in vitro and highlight the hurdles that need to be overcome to translate these promising approaches to the clinic. Striated muscles are highly organized tissues Fig.
The primary function of striated muscles is to generate force and contract in order to support respiration, locomotion, and posture skeletal muscle and to pump blood throughout the body cardiac muscle. 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.
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 Dq on the muscular adult dating river 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. Under light microscopy, striated muscles have highly ordered ultrastructure consisting of sarcomeres, which are basic contractile units containing a central myosin-rich dark anisotropic A band and two actin-dominated light isotropic I bands [ 1213 ].
While the sarcomeric proteins are conserved among cardiac and slow-twitch and fast-twitch skeletal muscles, the existence of specific isoforms of these proteins contributes to observed differences in rates of muscle contraction and relaxation [ 1415 ].
All types of striated muscle contain a branched network of membrane invaginations called T-tubules that enable synchronous calcium release throughout the entire cell volume. The T-tubules contact the sarcoplasmic reticulum SR between the A and I bands in skeletal muscle and at the Z-disc in cardiac muscle. Where the T-tubules and SR meet, the SR enlarges, fuses, and forms expanded chambers called terminal cisternae. In skeletal muscle the T-tubule meets with 2 terminal cisternae to form a triad, but only with a single terminal cisternae in cardiac muscle to form a diad.
The tri enable sufficient supply of calcium from SR to sustain tetanic contractions. Despite possessing the same functional units, the microscopic structures of skeletal and cardiac muscle fibers are different. Individual skeletal muscle fibers arise from the fusion of many muscle cells, producing multi-nucleated linear fibers, millimeters to centimeters in length Fig. In contrast, cardiac muscle consists of a cellular syncytium wherein individual cells are electromechanically interconnected in a branched pattern via specialized structures known as intercalated discs Fig.
Within the intercalated disc, gap junctions allow for a rapid propagation of electrical impulses Fig. Finally, while skeletal muscle fibers are directly innervated by motor neurons, cardiomyocytes are excited via a conduction cascade that begins with specialized pacemaking cells of the sinoatrial node and terminates at the ventricular cardiomyocytes. Skeletal muscle fibers are encased in a basement membrane rich in collagen IV, heparin sulfate proteoglycans HSPGsand laminin, which plays a key role in force transmission to the outer three connective tissue layers, the endo- peri- and epimysium.
In the heart, Collagen I is the main ECM protein made by cardiac fibroblasts that until recently were believed to be the most dominant cell type in the heart, with different abundances reported in different species [ 25 — 27 ]. While evidence for electrical coupling between fibroblasts and cardiomyocytes is present in vitro [ 2930 ], the ability of these cell types to form functional heterocellular gap junctions in vivo is still widely debated [ 3132 ].
Both in skeletal and cardiac muscles, blood is delivered to cells in a hierarchical manner with primary arteries progressively bunching into smaller vessels and capillaries [ 3334 ]. Greater capillary density is found in slow-oxidative than fast-glycolytic muscles [ 135 ] and in epicardium compared to endocardium with an average of 1.
Skeletal muscle force output is primarily achieved by summation and motor unit recruitment. Slow 10—30Hz and fast 50—Hz fibers achieve peak force at different frequencies due to the speed of contraction and relaxation Fig. Although lacking a tetanic response characteristic of skeletal muscle, the human heart still displays a positive force-frequency relationship Fig. Furthermore, force generation in skeletal muscle is typically controlled by motor unit recruitment, in order from smallest to largest, which in an exponential increase in force and enables a single muscle to produce both delicate and explosive movements [ 39 ].
Both skeletal and cardiac Dq on the muscular adult dating river display a biphasic force-length relationship, which is, in part, explained by the sliding filament theory [ 40 ]. Lengthening of the muscle increases the overlap of myosin and actin filaments within each sarcomere, which produces a higher contractile force during the power stroke of the contraction cycle.
However, in cardiac muscle the predominant cellular basis for the force-length relationship is the increased affinity of troponin C to calcium, which yields opening of additional sites for binding of myosin to actin and permits greater force generation [ 41 ]. In contrast to skeletal muscle, which operates close to the peak of its active force-length curve, cardiac muscle operates on the ascending part of the curve to allow stronger pumping for increased ventricular filling Fig. In response to injury, adult skeletal muscle exhibits robust regenerative response that involves a highly orchestrated action of multiple cell types.
During embryogenesis, myogenic transcription factors Myf5 and Mrf4 are transiently expressed to give rise to a ificant of SCs that persist throughout development [ 4546 ]. In adult muscle, SCs are a heterogeneous population with the majority of cells expressing Myf5 and being able to directly commit to myogenic differentiation [ 47 ]. SCs not expressing Myf5 preferentially self-renew and fill the SC niche but can divide asymmetrically to express Myf5 and support myogenesis [ 4748 ].
Regardless, the maintenance of SCs in adult muscle is dependent upon Myf5 highlighting the complex non-hierarchical regulatory network that controls SC stemness [ 49 ]. In response to injury and exercise, SCs that are typically quiescent become activated and contribute to muscle repair, as reviewed elsewhere [ 450 ].
Regenerative process in skeletal muscle is controlled primarily by the innate immune response Fig. During the first stage of muscle repair, infiltrated neutrophils promote degeneration of muscle fibers while M1 macrophages stimulate a pro-inflammatory cytokine release and muscle cell lysis [ 5556 ]. Subsequently, the SCs undergo activation and differentiation, which is followed by ECM deposition, angiogenesis to revascularize regenerating tissue, and reinnervation of the new myofibers. Proliferating SCs also migrate bi-directionally along the longitudinal but not the horizontal axis of the degenerating fibers to aid in the redistribution of regenerating muscle progenitors [ 57 ].
Conversion to an M2 macrophage phenotype is critical for the repair process as it shifts SCs towards differentiation and away from proliferation seen predominantly with M1 macrophages [ 58 ].
Among the other cell types important for successful muscle regeneration, fibroadipogenic progenitors FAPs are known to promote myofiber formation through controlled ECM deposition and paracrine factors [ 5960 ]. A Damage to skeletal muscle 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 in death of cardiomyocytes CMsan initial infiltration of neutrophils and upregulation of matrix metalloproteinases.
C Striated muscle repair can be augmented via exogenous delivery of single cells, biomaterials with or without cells, as well as transplantation Dq on the muscular adult dating river in vitro engineered functional muscle tissues. In contrast to skeletal muscle, the adult mammalian heart lacks robust regenerative potential [ 561 ].
However, shortly after birth mammalian hearts can still regenerate, as recently shown in the case of a newborn child with myocardial infarction [ 62 ]. In neonatal mice, this regenerative process is associated with the activation of epicardial-specific genes, angiogenesis, and a global proliferation of existing cardiomyocytes that restores cardiac function [ 63 ] and is dependent upon infiltration of neonatal macrophages [ 64 ].
In contrast, cardiac injury in adult heart produces a primarily fibrotic scar that le to a decline in function. The early remodeling phase consists of neutrophil infiltration, activation of matrix metalloproteinasaes and early degradation of extracellular matrix ECMwhich le to wall thinning and ventricular dilation. Pathological hypertrophy also develops as an adaptive response to the decreased contractile function and is largely initiated by the myofiber stretch following chamber dilation and neurohormonal activation, in particular via combined actions of norepinephrine, endothelin-1, and angiotensin II [ 65 ].
In contrast to certain amphibians [ 66 ] and fish [ 67 ], the endogenous repair mechanisms in mammalian skeletal muscle can only regenerate a finite amount of muscle tissue and can thus be overwhelmed by the deposition of fibrotic scar following volumetric muscle loss resulting from trauma or large resection [ 68 ]. Furthermore, in sarcopenia, skeletal muscle mass, function, and regenerative ability decrease with age and can cause or exacerbate health problems [ 6970 ]. Sarcopenia is characterized by a muscular atrophy, loss of muscle fibers, decreased and size of motor units, and increased fibrosis and fat accumulation [ 71 — 74 ], and can likely be attributed to SC depletion and impaired SC function.
Inhibition of p38 MAPK restores the regenerative potential of aged SCs, and can restore force generation of muscles in aged mice to levels found in younger animals [ 7576 ]. Similar to skeletal muscle, impaired function of cardiac muscle can arise from various congenital or acquired diseases. In ischemic heart disease, the leading cause of morbidity and mortality in the world [ 77 ], the buildup of atherosclerotic plaques within coronary arteries increases with age and can cause tissue ischemia or necrosis myocardial infarction upon rupture, which can precipitate into congestive heart failure over time.
Numerous myopathies, including autoimmune and viral myocarditis, can similarly lead to heart failure if left untreated.
Diastolic cardiac dysfunction occurs due to pathological hypertrophy and stiffening of the heart walls that impairs chamber relaxation and filling during the cardiac cycle. The long-standing hypertension, ischemic injuries, aging, and aortic stenosis, as wells as certain metabolic diseases such as glycogen storage disease [ 78 ] can all cause diastolic dysfunction. Lastly, congenital heart defects CHDs are the most common type of birth defect and represent the leading cause of mortality in infants [ 7980 ].
Three of the top five common types Dq on the muscular adult dating river CHDs—ventricular septal defects, Tetrology of Fallot, and atrial septal defects—all contain a defect in the heart wall that requires surgical correction when sufficiently large, and often multiple surgeries due to failed or inadequate grafts [ 81 ]. Since a large of proteins are expressed in all striated muscles, the same genetic defect can result in both cardiac and skeletal muscle disease.
For example, mutations of proteins in the dystrophin-associated glycoprotein complex DGC or associated ECM proteins such as laminin and merosin can lead to a wide range of muscular dystrophies [ 82 ]. The DGCs link the sarcomeres to the ECM and are involved in the transmission of force and protection of the membrane from shear stress [ 83 ]. Still, not all skeletal muscles are affected equally by muscular dystrophy, with the ocular muscles being typically spared [ 85 ], but the diaphragm which is in constant use being the most severely affected muscle [ 86 ] and load-bearing muscles such as the gluteus maximus and the posterior muscles of the lower legs [ 8788 ] also being severely affected.
Furthermore, different diseases can affect cardiac and skeletal muscles differently. Duchenne Muscular dystrophy DMDthe most severe form of muscular dystrophy characterized by the complete loss of functional dystrophin, typically has a more severe skeletal muscle phenotype and a milder cardiac phenotype [ 89 ]. The first cell-based approaches to improve function of injured or diseased striated muscles involved transplantation of stem or progenitor cells into the site of tissue damage. These strategies require expanding a suitable cell population in vitro to generate sufficient cell s for transplantation.
The desired characteristics of the expanded cells would be to: 1 Retain innate stemness or myogenicity during in vitro culture, 2 Be immuno-privileged to obviate a need for long-term immunosuppression, 3 Survive and robustly engraft upon transplantation, 4 Structurally and functionally integrate with host tissue, 5 Repopulate and replenish the tissue-resident stem cell niches and 6 Permanently improve muscle function following transplantation. Additionally, having cells that can be delivered throughout the circulatory system and efficiently home to damaged tissues would be desirable to avoid damage due to multiple intramuscular injections and when needed enable the uniform distribution of cells throughout the entire organ.Dq on the muscular adult dating river
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Striated Muscle Function, Regeneration, and Repair