15.4 Skeletal muscle engineering and therapies
8 min read•july 30, 2024
Skeletal muscle engineering is a cutting-edge field that aims to repair and regenerate damaged muscle tissue. It combines cell biology, biomaterials, and stimulation techniques to create functional muscle constructs for treating injuries and diseases.
This exciting area of research explores various cell sources, scaffolds, and stimulation methods to engineer muscle tissue. From to stem cells, and from electrical to mechanical stimulation, scientists are developing innovative approaches to restore muscle function and treat conditions like muscular dystrophies.
Skeletal muscle regeneration mechanisms
Cellular processes in muscle regeneration
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Top images from around the web for Cellular processes in muscle regeneration
Frontiers | Adult Muscle Stem Cells: Exploring the Links Between Systemic and Cellular Metabolism View original
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- Skeletal muscle regeneration is a complex process involving the activation, proliferation, and differentiation of satellite cells, the resident stem cells of skeletal muscle tissue
- Upon injury, satellite cells are activated and undergo asymmetric division, giving rise to that proliferate and differentiate into myocytes
- Myocytes fuse together to form multinucleated myotubes, which further mature into functional muscle fibers
Molecular regulation of muscle regeneration
- The process of skeletal muscle regeneration is regulated by various growth factors, such as hepatocyte growth factor (HGF), insulin-like growth factor 1 (IGF-1), and fibroblast growth factor (FGF)
- HGF stimulates satellite cell activation and proliferation
- IGF-1 promotes myoblast differentiation and
- FGF enhances satellite cell proliferation and inhibits differentiation
- Extracellular matrix (ECM) remodeling, involving the degradation of damaged ECM and the synthesis of new ECM components, is crucial for successful skeletal muscle regeneration
- Matrix metalloproteinases (MMPs) degrade damaged ECM, allowing for cell migration and new tissue formation
- Tissue inhibitors of metalloproteinases (TIMPs) regulate MMP activity to prevent excessive ECM degradation
- Macrophages play a key role in skeletal muscle regeneration by removing cellular debris, secreting growth factors, and modulating the inflammatory response
- M1 macrophages initiate inflammation and clear damaged tissue
- M2 macrophages promote tissue repair and regeneration
- The Wnt/β-catenin signaling pathway is involved in regulating satellite cell proliferation and differentiation during skeletal muscle regeneration
- promotes satellite cell self-renewal and maintains their stemness
- β-catenin accumulation in the nucleus activates target genes involved in myogenic differentiation
Cell sources for muscle engineering
Primary cell sources
- Satellite cells, the resident stem cells of skeletal muscle, are a primary cell source for skeletal muscle tissue engineering due to their ability to proliferate and differentiate into functional muscle fibers
- Satellite cells can be isolated from muscle biopsies and expanded in vitro
- Challenges include limited proliferative capacity and loss of stemness during expansion
- Myoblasts, the committed progenitors of muscle cells, can be derived from satellite cells and used for muscle engineering
- Myoblasts have a higher proliferative capacity than satellite cells
- Myoblasts are more committed to the myogenic lineage and may have reduced regenerative potential
Alternative cell sources
- Mesenchymal stem cells (MSCs) derived from various tissues, such as bone marrow, adipose tissue, and umbilical cord, have been explored as an alternative cell source for skeletal muscle regeneration due to their multipotency and immunomodulatory properties
- MSCs can differentiate into myogenic cells under appropriate conditions
- MSCs secrete paracrine factors that promote muscle regeneration and modulate inflammation
- Induced pluripotent stem cells (iPSCs) can be differentiated into myogenic progenitors and used for skeletal muscle tissue engineering, offering the potential for patient-specific therapies
- iPSCs are derived from adult somatic cells and reprogrammed to a pluripotent state
- iPSC-derived myogenic progenitors can be expanded and differentiated into functional muscle cells
- Embryonic stem cells (ESCs) have the potential to differentiate into any cell type, including myogenic cells
- ESC-derived myogenic progenitors can be used for muscle engineering
- Ethical concerns and the risk of teratoma formation limit the use of ESCs in clinical applications
Biomaterials for muscle engineering
- Natural biomaterials, such as collagen, fibrin, and decellularized extracellular matrix (dECM), provide a biocompatible and biodegradable scaffold for skeletal muscle tissue engineering, mimicking the native muscle microenvironment
- Collagen is the most abundant protein in the ECM and supports cell adhesion and growth
- Fibrin, derived from blood clotting, forms a gel-like scaffold and promotes cell migration and
- dECM, obtained by removing cells from native tissue, retains the complex composition and structure of the native ECM
- Synthetic biomaterials, including polyesters (PLGA, PCL) and (PEG, PEGDA), offer tunable mechanical and degradation properties for skeletal muscle tissue engineering
- Polyesters provide mechanical strength and can be fabricated into aligned fibers to guide muscle cell orientation
- Hydrogels mimic the hydrated nature of the ECM and allow for the encapsulation of cells and bioactive molecules
- Hybrid scaffolds, combining natural and synthetic biomaterials, can be designed to leverage the advantages of both material types, such as bioactivity and mechanical strength
- Collagen-polyester composite scaffolds provide both biological cues and mechanical support
- Fibrin-PEG hydrogels offer a cell-friendly environment with tunable mechanical properties
- Alignment of biomaterial fibers or the incorporation of topographical cues can guide the orientation of muscle cells and promote the formation of aligned muscle fibers
- Electrospinning can produce aligned nanofiber scaffolds that mimic the anisotropic structure of native muscle
- Microgrooved surfaces can induce muscle cell alignment and promote the formation of organized muscle bundles
Stimulation for muscle regeneration
Electrical stimulation
- Electrical stimulation mimics the natural activation of skeletal muscle by motor neurons, promoting the differentiation and maturation of muscle cells in tissue-engineered constructs
- Electrical pulses depolarize the cell membrane and activate voltage-gated calcium channels, leading to muscle contraction
- Chronic low-frequency electrical stimulation (CLFS) promotes the expression of slow-twitch muscle proteins and enhances fatigue resistance
- Applying electrical stimulation to tissue-engineered skeletal muscle constructs enhances the formation of sarcomeres, the contractile units of muscle fibers, leading to improved contractile function
- Electrical stimulation increases the expression of sarcomeric proteins, such as myosin heavy chain and α-actinin
- Electrically stimulated muscle constructs exhibit higher force generation and improved calcium handling compared to unstimulated controls
Mechanical stimulation
- Mechanical stimulation, such as cyclic stretching or loading, simulates the physiological forces experienced by skeletal muscle during normal activity, promoting muscle cell alignment, differentiation, and hypertrophy
- Cyclic stretching applies tensile strain to muscle cells, mimicking the stretch-induced hypertrophy observed in vivo
- Mechanical loading, such as compression or fluid shear stress, can be applied to muscle constructs to simulate the forces experienced during muscle contraction
- Mechanical stimulation activates mechanotransduction pathways, such as the FAK and MAPK signaling cascades, which regulate gene expression and protein synthesis in muscle cells
- Focal adhesion kinase (FAK) is activated by mechanical stress and promotes the assembly of focal adhesions, which link the cytoskeleton to the ECM
- Mitogen-activated protein kinase (MAPK) pathways, such as ERK1/2 and p38, are activated by mechanical stimuli and regulate the expression of genes involved in muscle growth and differentiation
Combined stimulation and optimization
- The combination of electrical and mechanical stimulation can synergistically enhance the maturation and functionality of tissue-engineered skeletal muscle constructs
- Electrical stimulation induces muscle contraction, while mechanical stimulation provides the resistance necessary for muscle growth
- Combined stimulation promotes the alignment and organization of muscle fibers, leading to improved contractile properties
- The timing, duration, and intensity of electrical and mechanical stimulation need to be optimized to achieve the desired outcomes in skeletal muscle regeneration and maturation
- Continuous or intermittent stimulation protocols can be employed, depending on the stage of muscle development
- The frequency, amplitude, and duration of stimulation pulses can be modulated to mimic different muscle fiber types (slow-twitch vs. fast-twitch)
- Bioreactor systems that incorporate electrical and mechanical stimulation can provide a controlled environment for the cultivation and maturation of tissue-engineered skeletal muscle constructs
- Perfusion bioreactors can deliver nutrients and oxygen to the developing muscle tissue while applying mechanical stimulation
- Electrical stimulation can be integrated into bioreactor systems using electrodes or conductive scaffolds
Muscle engineering for treatment
Volumetric muscle loss and muscular dystrophies
- Skeletal muscle tissue engineering holds promise for treating volumetric muscle loss (VML) injuries, where large portions of muscle tissue are lost due to trauma or surgery, by providing functional muscle tissue substitutes
- VML results in a permanent loss of muscle mass and function, as the endogenous regenerative capacity of skeletal muscle is overwhelmed
- Tissue-engineered muscle constructs can be implanted into the injury site to replace lost muscle tissue and restore function
- Tissue-engineered skeletal muscle constructs can be used to treat muscular dystrophies, such as Duchenne muscular dystrophy (DMD), by replacing damaged muscle tissue with healthy, engineered muscle fibers
- DMD is caused by mutations in the dystrophin gene, leading to progressive muscle weakness and degeneration
- Engineered muscle tissue derived from healthy cells or genetically corrected autologous cells can be used to replace damaged muscle in DMD patients
Gene therapy and sarcopenia
- Gene therapy approaches can be combined with skeletal muscle tissue engineering to correct genetic defects in muscle cells before implantation, offering a potential treatment for inherited muscular disorders
- Viral vectors, such as adeno-associated viruses (AAVs), can be used to deliver therapeutic genes to muscle cells
- CRISPR/Cas9 gene editing can be employed to correct disease-causing mutations in muscle cells derived from patients with inherited muscular disorders
- Skeletal muscle tissue engineering can aid in the treatment of sarcopenia, the age-related loss of muscle mass and strength, by providing a source of functional muscle tissue to replace lost or atrophied muscle
- Sarcopenia contributes to frailty and increased risk of falls in the elderly population
- Implantation of tissue-engineered muscle constructs can help maintain muscle mass and strength in older individuals
In vitro models and clinical translation
- Tissue-engineered skeletal muscle constructs can serve as in vitro models for drug screening and toxicity testing, accelerating the development of new therapies for muscular disorders
- Three-dimensional (3D) muscle constructs better recapitulate the native muscle environment compared to traditional 2D cell culture
- Disease-specific muscle models can be generated using cells derived from patients with muscular disorders, enabling personalized drug screening
- The integration of tissue-engineered skeletal muscle with the host vasculature and nervous system remains a challenge that needs to be addressed to ensure the long-term survival and functionality of implanted muscle tissue
- Vascularization is critical for the survival of large muscle constructs, as diffusion alone is insufficient to maintain cell viability
- Innervation of engineered muscle tissue is necessary for proper muscle function and to prevent atrophy
- Clinical translation of skeletal muscle tissue engineering requires further optimization of cell sources, biomaterials, and stimulation protocols, as well as rigorous safety and efficacy testing in preclinical and clinical studies
- Standardized manufacturing processes and quality control measures need to be established to ensure the consistency and safety of tissue-engineered muscle products
- Long-term studies in animal models are necessary to evaluate the survival, integration, and functionality of implanted muscle constructs
- Clinical trials will be required to demonstrate the safety and efficacy of skeletal muscle tissue engineering approaches in human patients
Key Terms to Review (18)
Angiogenesis: Angiogenesis is the physiological process through which new blood vessels form from pre-existing ones, playing a critical role in growth, development, and wound healing. This process is essential for providing nutrients and oxygen to tissues, particularly in the context of tissue regeneration and repair, where it supports cellular survival and function.
Decellularized Matrices: Decellularized matrices are scaffolds created by removing cellular components from tissues or organs while preserving the extracellular matrix (ECM) structure and composition. This process retains important biochemical and mechanical properties that are essential for tissue engineering, particularly in skeletal muscle engineering and therapies, as it provides a natural environment that supports cell attachment, growth, and differentiation.
Electromyography: Electromyography (EMG) is a diagnostic procedure that assesses the electrical activity of skeletal muscles through the use of electrodes. By detecting and recording the electrical signals generated by muscle fibers when they are activated, EMG provides crucial information about muscle health and function. This technique is particularly relevant in skeletal muscle engineering and therapies, as it helps in understanding muscle responses to various stimuli and conditions, guiding interventions for muscle repair and regeneration.
Force generation testing: Force generation testing is a method used to evaluate the ability of skeletal muscle tissues or engineered muscle constructs to produce force under various conditions. This testing is crucial for assessing the functionality and performance of muscle tissues, particularly in regenerative medicine, where the goal is to restore or enhance muscle function through engineering approaches or therapies.
Functional tissue replacement: Functional tissue replacement refers to the process of restoring or replacing damaged or lost tissues in the body using engineered tissues or biomaterials that replicate the natural function and structure of the original tissue. This approach aims not just to fill a void but to restore normal tissue functionality, which is crucial in therapies for conditions such as muscle injuries or degenerative diseases.
Hydrogels: Hydrogels are three-dimensional, hydrophilic polymeric networks capable of holding large amounts of water while maintaining their structure. Their unique ability to absorb water makes them ideal for various biomedical applications, particularly in regenerative medicine, where they can serve as scaffolds for cell growth and tissue engineering.
Muscle atrophy: Muscle atrophy is the process of muscle wasting or decrease in muscle mass, often due to disuse, aging, or specific diseases. It leads to a reduction in muscle strength and function, affecting physical performance and overall health. Understanding muscle atrophy is essential for developing strategies in skeletal muscle engineering and therapies aimed at enhancing muscle recovery and growth.
Muscle hypertrophy: Muscle hypertrophy refers to the increase in muscle size and cross-sectional area due to the growth of muscle fibers. This process occurs primarily in response to resistance training or weightlifting, where the muscle fibers experience micro-tears that stimulate repair mechanisms, leading to greater muscle mass and strength over time. Muscle hypertrophy is crucial in various therapeutic applications, especially in regenerative medicine, where enhancing muscle function and recovery is a key focus.
Muscle tissue scaffolding: Muscle tissue scaffolding refers to a three-dimensional framework designed to support the growth and regeneration of muscle cells. This scaffold provides a suitable environment for muscle cells to adhere, proliferate, and differentiate, mimicking the natural extracellular matrix found in skeletal muscle. The design of these scaffolds is critical in developing effective therapies for muscle injuries or degenerative diseases.
Myoblasts: Myoblasts are specialized, embryonic muscle precursor cells that play a critical role in the formation and repair of skeletal muscle tissue. These cells are capable of proliferation and differentiation into myocytes, which are the building blocks of muscle fibers. Understanding myoblasts is essential for developing therapies related to muscle injuries and degenerative diseases.
Myofibrillogenesis: Myofibrillogenesis is the biological process by which myofibrils, the contractile units of muscle fibers, are formed and organized within developing muscle cells. This process is crucial for the proper structure and function of skeletal muscle, as it ensures that myofibrils align correctly to enable efficient contraction and force generation. Understanding myofibrillogenesis is essential for advancements in muscle engineering and therapies aimed at repairing or replacing damaged skeletal muscle tissue.
Myogenesis: Myogenesis is the process of muscle formation, specifically the development of muscle fibers from precursor cells known as myoblasts. This biological process is crucial for skeletal muscle development and regeneration, as it involves the differentiation of these myoblasts into multinucleated myotubes, which then mature into functional muscle fibers. Understanding myogenesis is essential for developing effective skeletal muscle engineering and therapies aimed at repairing or enhancing muscle tissue.
Notch pathway: The Notch pathway is a fundamental cell signaling mechanism that regulates various developmental processes, including cell fate determination, differentiation, and proliferation. This pathway plays a crucial role in cellular communication and influences how cells respond to their environment, especially in the development and maintenance of tissues like skeletal muscle.
Robert Langer: Robert Langer is a prominent biomedical engineer known for his pioneering work in drug delivery systems and biomaterials. His innovative research has significantly advanced the fields of tissue engineering and regenerative medicine, impacting how therapies are developed and delivered. Langer's contributions to surface chemistry, immunology, skeletal muscle engineering, and growth factor application have led to new treatments and technologies that enhance healing and tissue regeneration.
Satellite cells: Satellite cells are a type of stem cell located in skeletal muscle tissue that play a critical role in muscle regeneration and repair. These cells are positioned between the basal lamina and the plasma membrane of muscle fibers, and they become activated in response to muscle injury or stress. Once activated, satellite cells can proliferate and differentiate into new muscle fibers or fuse with existing fibers, making them essential for muscle growth and recovery.
Takahashi Kizaki: Takahashi Kizaki is a notable figure in the field of regenerative medicine, particularly recognized for his contributions to skeletal muscle engineering. His work focuses on the application of stem cell technologies and tissue engineering to develop therapies aimed at repairing and regenerating damaged skeletal muscle tissue, which is crucial for recovery from injuries and muscular dystrophies.
Treatment of muscular dystrophy: The treatment of muscular dystrophy involves a range of strategies aimed at managing symptoms, improving quality of life, and slowing disease progression. These treatments can include physical therapy, medications, surgical interventions, and emerging therapies such as gene therapy and stem cell therapy. Understanding the various approaches to treatment is crucial for enhancing muscle function and overall patient well-being.
Wnt signaling: Wnt signaling is a complex cell communication pathway that plays a crucial role in regulating various cellular processes such as cell proliferation, differentiation, and migration. It is essential in maintaining stem cell niches and influencing the behavior of cells within their microenvironments, as well as being involved in ECM remodeling and the development of biomaterials. This pathway has significant implications in tissue engineering and regenerative medicine, particularly in skeletal muscle development and repair.