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Myotoxin

Myotoxins are small proteins or peptides found predominantly in the venoms of viperid and elapid snakes, such as rattlesnakes (Crotalus spp.) and cobras (Naja spp.), as well as in some lizard venoms and bacterial exotoxins, that specifically target and induce irreversible necrosis in skeletal muscle tissue (myonecrosis). These toxins, often structurally related to phospholipases A₂ (PLA₂), disrupt the integrity of the muscle cell membrane (sarcolemma), leading to uncontrolled influx of ions like calcium and sodium, cellular degeneration, edema, hemorrhage, and eventual cell death. Myotoxins are a major contributor to the pathology of snakebites, causing severe local tissue damage, pain, swelling, and systemic complications including rhabdomyolysis (breakdown of muscle fibers), myoglobinuria, and potentially fatal acute renal failure. Structurally, myotoxins encompass diverse types, with many classified as PLA₂ homologs, including enzymatic Asp49 variants that hydrolyze phospholipids and non-enzymatic Lys49 variants that act through direct membrane binding via cationic and hydrophobic regions. Notable examples include crotamine, a low-molecular-weight basic from the South American ( terrificus), which also affects sodium channels, and myotoxin a from the prairie (Crotalus viridis viridis), both exemplifying the toxin's ability to cause rapid muscle damage without enzymatic activity. Other variants, such as cardiotoxins from elapid venoms and β-defensin-like , may additionally induce or affect , broadening their cytotoxic impact. The pathological timeline of myotoxin action typically begins with and hyperemia within 1 hour of , progressing to muscle fiber degeneration by 1–3 hours, overt by 6–24 hours, and partial regeneration over 3–28 days, often resulting in permanent tissue loss and if untreated. In clinical contexts, myotoxins account for significant morbidity in the estimated 5.4 million annual snakebites worldwide, with therapies targeting PLA₂ components showing variable efficacy, underscoring the need for targeted research into their mechanisms for improved treatments.

Overview

Definition

Myotoxins are naturally occurring proteins or peptides that cause irreversible damage to fibers, resulting in a pathological condition known as myonecrosis. These toxins are primarily identified by their ability to disrupt integrity, leading to and degeneration without affecting other major physiological systems in the same targeted manner. Unlike neurotoxins, which specifically impair function and synaptic , or hemotoxins, which disrupt clotting and vascular integrity, most myotoxins exert their effects predominantly on tissue, sparing direct neurotoxic or coagulopathic interference, though some, such as crotamine, exhibit additional effects on sodium channels. This specificity arises from their structural adaptations that favor interactions with muscle cell membranes, promoting localized necrosis while minimizing systemic impacts on neural or hematologic pathways. Myotoxins generally possess basic biochemical properties, with an isoelectric point (pI) exceeding 9, conferring a cationic character that enhances binding to negatively charged cellular membranes. Many snake venom myotoxins, particularly phospholipase A₂ (PLA₂) homologs, consist of 120-140 amino acids with molecular weights of 13-16 kDa, enabling efficient diffusion and penetration into muscle tissue upon exposure, though sizes vary across types such as smaller peptides like crotamine or larger bacterial exotoxins. These characteristics are conserved among PLA₂-like myotoxins from diverse biological origins, such as certain snake venoms and bacterial exotoxins.

Historical Discovery

The initial isolation of myotoxins from snake venoms occurred in the 1970s, with key work on crotaline species. In 1976, a myotoxic component was purified from the venom of the prairie rattlesnake (Crotalus viridis viridis) using gel filtration and ion-exchange chromatography, demonstrating its ability to induce skeletal muscle necrosis through disruption of muscle fiber integrity. This was followed by the characterization of myotoxin a, a basic polypeptide lacking enzymatic activity, isolated from the same venom source in 1977, highlighting early recognition of non-enzymatic myotoxic mechanisms. Advancements in the 1980s focused on phospholipases A2 (PLA2) from pit viper venoms, particularly in Bothrops species. A neutral, catalytically active Asp49 PLA2, termed myotoxin I, was isolated from Bothrops asper venom in 1984 via ion-exchange and gel filtration chromatography, confirming its myotoxic effects on skeletal muscle independent of broader venom components. Subsequently, in 1989, myotoxin II—a basic, catalytically inactive Lys49 PLA2 homologue—was purified from the same venom using CM-Sephadex chromatography, establishing that myotoxic potency could occur without phospholipase activity, as the toxin induced rapid muscle damage through membrane perturbation. These isolations from crotaline snakes underscored the diversity of myotoxins and their role in envenomation pathology. Earlier, in the late 1960s, myotoxic components were identified in elapid venoms, with cardiotoxins—small basic peptides from ( spp.) venoms—isolated and characterized for their ability to cause depolarization and in skeletal and . The 1990s brought structural insights via , revealing key features of myotoxin-membrane interactions. In 1990, the 2.0 Å crystal structure of a Lys49 PLA2 from the cottonmouth snake () venom was determined, identifying hydrophobic and cationic residues in the membrane-binding interface that facilitate myotoxicity despite lacking catalytic function. This work, along with subsequent studies on myotoxins, provided a foundational understanding of how structural motifs enable . In the , research expanded to bacterial sources, identifying myotoxins beyond venoms. The alpha-toxin of , a known since the early for causing myonecrosis in , was re-characterized in modern studies for its membrane-damaging mechanisms akin to snake myotoxins, with key papers in the 2000s elucidating its role in ion imbalance and tissue destruction.

Biological Sources

Snake Venoms

Myotoxins are primarily sourced from the venoms of snakes in the Viperidae family, particularly the Crotalinae subfamily of pit vipers, where they form key components of the venom proteome. In species such as Bothrops asper, these toxins represent a significant proportion of the venom, contributing substantially to its overall toxicity profile. For instance, Crotalus durissus produces crotamine, a well-characterized β-defensin-like myotoxin that can comprise a significant proportion of the venom protein content (up to around 20–30% in some populations). While less prevalent in the Elapidae family, certain cardiotoxins from cobra venoms (Naja spp.) exhibit overlapping myotoxic activity, inducing muscle damage alongside their primary cardiotoxic effects. Evolutionarily, myotoxins in these venoms aid in prey immobilization by inducing rapid skeletal muscle necrosis and paralysis, while also promoting tissue degradation to facilitate enzymatic digestion. Such toxins are documented in numerous viper species across the , with notably higher concentrations observed in pit vipers like those in the genera Bothrops and Crotalus.

Lizard Venoms

Myotoxins are also found in the venoms of certain lizards, particularly in the family , which includes the (Heloderma suspectum) and the Mexican beaded lizard (Heloderma horridum). These venoms contain small basic peptides with myotoxic properties similar to those in snake venoms, contributing to local tissue damage and following . Helodermatid myotoxins are structurally related to β-defensin-like peptides and play a role in prey subjugation and defense.

Bacterial Toxins

Bacterial myotoxins are exotoxins secreted by , primarily during anaerobic infections, that target tissue and contribute to in wound-related infections. These toxins are released by vegetative cells of the as they proliferate in hypoxic environments, such as deep traumatic wounds contaminated with or feces, facilitating rapid tissue destruction to promote bacterial spread. The primary bacterial source of myotoxins is Clostridium perfringens, a Gram-positive, spore-forming anaerobe responsible for clostridial myonecrosis (gas gangrene). Its alpha-toxin, a zinc-dependent phospholipase C (also known as lecithinase), hydrolyzes phosphatidylcholine in cell membranes, leading to muscle cell lysis and necrosis. This toxin is produced by all strains of C. perfringens and is the principal virulence factor in type A infections. Complementing alpha-toxin is perfringolysin O, a cholesterol-dependent cytolysin that forms pores in host cell membranes, enhancing tissue damage through cytolysis and synergizing with alpha-toxin to accelerate myonecrosis. These exotoxins are encoded by chromosomal genes (plc for alpha-toxin and pfoA for perfringolysin O) and expressed under anaerobic conditions typical of infected wounds. Myotoxins from other bacteria are rare. For example, in infections caused by (group A ), such as , toxins like streptolysin S contribute to cytolytic tissue damage that can affect muscle integrity, though its role is secondary to other virulence factors. Clostridial myonecrosis, driven by these toxins, occurs in fewer than 2% of traumatic wounds contaminated with clostridial spores, with higher historical rates in wartime injuries but reduced incidence due to modern wound management. Globally, this reflects the low progression rate from contamination—seen in up to 90% of open wounds—to overt myonecrosis, underscoring the toxin's pivotal role in .

Classification

Phospholipase A2-Like Myotoxins

Phospholipase A2-like myotoxins constitute the predominant family of myotoxins in snake venoms, exhibiting structural homology to secretory phospholipase A2 (sPLA2) enzymes while frequently displaying catalytically inactive properties. These proteins are primarily derived from viperid species and are responsible for inducing skeletal muscle necrosis through non-enzymatic mechanisms in many cases. Despite their structural similarity to functional sPLA2s, which hydrolyze phospholipids at the sn-2 position, the myotoxic variants often lack this enzymatic activity due to key amino acid substitutions at the catalytic site. Structurally, these myotoxins typically comprise 122–140 residues, forming a compact scaffold stabilized by seven conserved bonds that maintain the characteristic α/β fold of the sPLA2 superfamily. A conserved calcium-binding loop, involving residues such as Asp49 and coordinating Ca²⁺ ions, is present in catalytically active forms but modified in inactive variants, often rendering the loop non-functional for metal binding. High-resolution crystal structures of at least 11 such proteins have revealed a hydrophobic-hydrophilic interfacial recognition face (i-face), featuring residues like Leu2, Tyr28, and Lys69, which facilitate initial docking to membranes. For instance, the structure of the Lys49 variant BaspTX-II (PDB: 1Y4L) demonstrates a dimeric assembly with an extended conformation at the i-face, enabling membrane perturbation. The family is classified into two main structural variants based on the residue at position 49 in the catalytic center: Asp49 and Lys49. Asp49 myotoxins retain activity and require Ca²⁺ for , exemplified by myotoxin I (MT-I) from the of , which hydrolyzes phospholipids to contribute to tissue damage. In contrast, Lys49 myotoxins are catalytically inactive due to the substitution of for , coupled with other alterations like His48Gln, yet they induce myonecrosis via direct destabilization; a representative example is BaspTX-II from . These PLA2-like myotoxins constitute a major component, often comprising up to 70% of the protein content in viperid venoms. Beyond the genus, examples include the enzymatic PLA2 myotoxin-a from the prairie (Crotalus viridis viridis), a basic protein of 123 residues with 91% sequence identity to crotoxin B and potent myotoxic effects through plasma disruption. This dominance highlights their evolutionary adaptation as key effectors in , particularly in New World viperids.

Other Venom Myotoxins

Small myotoxins represent a distinct class of non-enzymatic peptides found in the venoms of certain species, characterized by their compact size and basic nature. These toxins typically consist of 42-45 residues cross-linked by three bridges, resulting in a stable, cationic with high isoelectric points that facilitate with biological membranes. For instance, myotoxin I, isolated from the venom of the prairie rattlesnake (), comprises 45 residues and lacks any enzymatic activity, distinguishing it from more prevalent (PLA2)-like myotoxins by its simpler scaffold and direct role in inducing local tissue damage without catalytic hydrolysis. Unlike PLA2 variants, which rely on enzymatic disruption for potency, small myotoxins exert their effects primarily through physical perturbation of cell surfaces. Cardiotoxins, belonging to the three-finger toxin (3FTx) family, are predominantly found in elapid snake venoms and exhibit dual functionality, with primary cardiotoxic effects extending to myotoxic activity on . These peptides feature a characteristic three-loop structure stabilized by four disulfide bonds, typically encompassing around 60 amino acid residues, which enables them to bind diverse receptors across tissue types. An example is cardiotoxin (CTX) from the (Naja naja), which, while optimized for disrupting cardiac channels, demonstrates on skeletal muscle fibers, leading to through destabilization rather than enzymatic means. This structural versatility sets cardiotoxins apart from viperid myotoxins, as their beta-sheet-dominated folds allow for broader pharmacological targeting compared to the helical-rich domains of PLA2 homologs. Crotamine stands out as a unique basic myotoxin in the venoms of South American rattlesnakes, particularly terrificus, due to its multifunctional profile that includes myotoxicity alongside and cell-penetrating capabilities. Composed of 42 residues with three bridges forming a compact, amphipathic structure rich in and , crotamine exhibits a high positive charge that promotes selective uptake into acidic cellular compartments. This differs from typical small myotoxins in North American rattlesnakes by incorporating additional beta-turn motifs that enhance its membrane translocation properties, enabling applications beyond such as .

Bacterial Myotoxins

Bacterial myotoxins encompass a range of toxins secreted by , particularly species of the genus Clostridium, that specifically target cells to induce through enzymatic degradation or membrane permeabilization. Unlike venom-derived myotoxins, which are often peptide-based, bacterial variants emphasize activity and cholesterol-dependent or independent formation as key mechanisms. These toxins contribute to severe infections like by disrupting cellular integrity and promoting bacterial spread. A prominent class of bacterial myotoxins includes phospholipases, with alpha-toxin from serving as the archetypal example. This toxin is a Zn²⁺-dependent that catalyzes the of , the predominant in eukaryotic membranes, yielding diacylglycerol and as products. The resulting diacylglycerol activates pathways, while the membrane perturbation leads to increased permeability and eventual lysis, distinguishing its enzymatic action from direct pore assembly. Cytolysins represent another critical category, exemplified by perfringolysin O from . This 53 kDa protein is a -dependent cytolysin that recognizes and binds to in bilayers, triggering rapid oligomerization into arc- and ring-shaped complexes comprising 30-50 monomers. These assemblies insert β-hairpins to form large transmembrane pores with diameters of 250-300 , facilitating massive influx, osmotic swelling, and primarily in -rich host cell membranes such as those of myocytes and erythrocytes. Among other bacterial myotoxins, alpha-toxin from exhibits pore-forming capabilities akin to perfringolysin O but with a broader cytolytic spectrum, enabling across diverse types through binding to GPI-anchored proteins and calcium influx. This versatility enhances its role in spontaneous myonecrosis during clostridial infections. These myotoxins collectively drive the local tissue destruction observed in , as elaborated in the pathological effects section.

Mechanism of Action

Membrane Binding and Disruption

Myotoxins, particularly the phospholipase A₂ (PLA₂)-like variants such as Lys49-PLA₂s from snake venoms, initiate their toxic effects through specific interactions with muscle cell membranes. These cationic toxins bind electrostatically to negatively charged phospholipids, such as phosphatidylserine and phosphatidic acid, in the outer leaflet of the plasma membrane. This binding is facilitated by the toxin's basic residues, including those in the C-terminal region, which form salt bridges with the anionic head groups of the lipids. The hydrophobic moment of amphipathic α-helices and segments within the toxin further stabilizes this interfacial adsorption, enhancing the initial docking. Structural features of Lys49-PLA₂s enable subsequent without enzymatic . The C-terminal region, rich in cationic and hydrophobic residues including , facilitates and disruption of the through non-covalent interactions. Unlike catalytically active Asp49-PLA₂s, these myotoxins lack dependency on Ca²⁺ ions for activity, owing to the substitution of aspartate at position 49 with , which abolishes the catalytic site while preserving membrane-disruptive capability. This Ca²⁺-independent mechanism allows efficient targeting of membranes rich in anionic . In contrast, enzymatic Asp49-PLA₂ myotoxins bind similarly but hydrolyze phospholipids at the sn-2 position, producing lysophospholipids and free fatty acids. These products disrupt integrity by altering fluidity, promoting fusion, and inducing further imbalances and cellular damage.

Ion Imbalance and Cell Death

Myotoxins, particularly phospholipase A₂ (PLA₂)-like proteins from snake venoms such as those of species, initiate imbalances by disrupting the , leading to rapid efflux of intracellular contents and influx of extracellular s. This disruption triggers a massive release of ATP and (K⁺) from muscle cells, with up to 60% of K⁺ efflux occurring within 5 minutes at concentrations of 50 μg/mL for Lys49 myotoxins like myotoxin II (Mt-II). Concurrently, there is substantial influx of calcium (Ca²⁺) and sodium (Na⁺) through the compromised , exacerbating cellular dysregulation; the released ATP further amplifies Ca²⁺ entry by activating P2X purinergic receptors on the cell surface. This Ca²⁺ overload subsequently activates endogenous proteases, such as calpains, and s, including Ca²⁺-dependent PLA₂ isoforms, which degrade structural proteins like desmin and , contributing to instability and enzymatic damage. The elevated cytosolic Ca²⁺ levels drive hypercontraction of skeletal muscle fibers by promoting actomyosin interactions in the contractile apparatus. This results in pronounced shortening of sarcomeres and the formation of characteristic delta lesions—wedge-shaped areas of intense contraction at the periphery of muscle fibers—observed within minutes of toxin exposure. Such hypercontraction disrupts the structural integrity of myofibrils, marking an early degenerative event in the myotoxic process. Downstream, these ion perturbations propel a necrotic pathway culminating in irreversible . Ca²⁺ overload induces mitochondrial swelling and dysfunction, impairing ATP production and triggering the generation of (ROS) through . The combined effects of , energy depletion, and ROS lead to plasma membrane rupture and myocyte , with predominating over in high-toxin scenarios typical of envenomations. No significant apoptotic dominance is observed in this context, distinguishing myotoxin-induced damage from other cytotoxic mechanisms.

Pathological Effects

Local Myonecrosis

Local myonecrosis refers to the acute destruction of at the site of myotoxin exposure, characterized by histopathological changes including pronounced , degeneration of muscle fibers, and a progressive inflammatory infiltrate. arises from increased and fluid accumulation in the , leading to swelling within hours of exposure. Muscle fiber degeneration manifests as hypercontraction, fragmentation, and loss of sarcoplasmic integrity, often resulting in up to 50% reduction in muscle fiber mass in severe experimental cases. The inflammatory response begins with infiltration peaking around 24 hours post-exposure, followed by predominance by day 3, which aids in debris clearance but contributes to further disruption. In snake envenomations, particularly from species, local myonecrosis presents as focal in the affected limbs, with extensive tissue damage due to the action of phospholipase A2-like myotoxins. These toxins disrupt membranes, inducing calcium influx and subsequent fiber confined to the injection site. Histopathological examination reveals with hyalinized fibers, minimal hemorrhage in pure myotoxic cases, and an intense leukocytic infiltrate that exacerbates local damage. Bacterial myotoxins, such as those produced by in clostridial myonecrosis, cause localized muscle destruction marked by gas formation and due to bacterial of tissues. Alpha-toxin, a lecithinase, hydrolyzes membrane phospholipids, leading to and at the infection site. shows widespread muscle fiber with gas bubbles within tissues, accompanied by polymorphonuclear infiltration and vascular , resulting in rapid compartmental syndrome-like progression.

Systemic Consequences

Myotoxins, upon systemic dissemination, induce widespread breakdown known as , leading to the release of and other intracellular contents into the circulation. This is a primary driver of (AKI), which manifests in 10-30% of severe envenomations involving myotoxic venoms such as those from viper species. further contributes to electrolyte imbalances, including from potassium leakage out of necrotic cells, and resulting from buildup and impaired renal acid excretion. Additionally, survivors of severe may develop in 37-41% of cases over 12-45 months post-envenomation. The extensive tissue destruction from myotoxins also provokes a systemic inflammatory cascade, characterized by a with marked elevations in proinflammatory mediators such as interleukin-6 (IL-6) and tumor factor-alpha (TNF-α). These cytokines, released in response to components like phospholipases A2, amplify endothelial damage, , and immune recruitment, potentially culminating in multi-organ dysfunction syndrome. In snakebites, for instance, this response mirrors acute trauma, with proinflammatory cytokines driving and . Bacterial myotoxins, particularly from in (clostridial myonecrosis), disseminate rapidly and trigger severe through alpha-toxin-mediated and tissue necrosis. Mortality rates range from 5-30% with prompt treatment, approaching 100% if untreated, often due to overwhelming toxemia and multi-organ failure within hours to days.

Clinical Aspects

Diagnosis

Diagnosis of myotoxin involvement typically relies on a combination of clinical presentation, laboratory biomarkers indicating muscle damage, imaging modalities to visualize tissue involvement, and specific assays to confirm the etiological agent. Biomarkers such as elevated serum creatine kinase (CK) levels, often exceeding 1000 U/L, serve as a primary indicator of myonecrosis, with CK-MM isoform particularly sensitive for early detection in myotoxic snake envenomations. Myoglobinuria, detected through urine dipstick or quantitative assays, reflects massive muscle breakdown and is a hallmark of rhabdomyolysis induced by myotoxins. Additionally, increased levels of lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and troponin (for potential cardiac muscle overlap) provide supportive evidence of widespread cellular damage. Imaging plays a crucial role in assessing the extent of muscle involvement. (MRI) is highly effective for detecting , on T2-weighted sequences, and necrotic changes in affected skeletal muscles, offering superior soft tissue contrast compared to other modalities. In cases of bacterial myotoxins, such as those from causing , can reveal characteristic hyperechoic foci with shadowing due to intramuscular gas, facilitating rapid bedside diagnosis. Specific laboratory tests enable targeted identification of myotoxin sources. Enzyme-linked immunosorbent assay () detects snake venom antigens in serum or urine, aiding in the confirmation of envenomation by myotoxic species like those from crotaline or elapid snakes. For bacterial etiologies, polymerase chain reaction () on wound swabs or tissue samples identifies clostridial toxin genes, such as those encoding alpha-toxin, providing definitive etiological diagnosis. Systemic markers of , including and indicators, may accompany severe myotoxin exposure but require integration with the above for comprehensive evaluation.

Treatment Strategies

Treatment strategies for myotoxin-induced injuries vary depending on the source, with serving as the cornerstone for myotoxins and a combination of surgical, , and adjunctive therapies for bacterial myotoxins. For venom myotoxins, particularly those from viper species like , polyvalent equine (IgG) antivenoms are the primary intervention, effectively neutralizing myotoxic effects when administered early after . These antivenoms, produced by hyperimmunizing horses with s from multiple species, can prevent or reverse tissue damage if given within hours of the bite, as demonstrated in experimental models of where early significantly reduced myonecrosis and release. Typical initial dosing ranges from 100 to 200 ml intravenously, titrated based on clinical response and dose, though efficacy diminishes if delayed beyond 6 hours due to irreversible muscle binding of the toxins. In cases of bacterial myotoxins, such as those produced by Clostridium perfringens in gas gangrene (clostridial myonecrosis), treatment emphasizes prompt surgical debridement to remove necrotic tissue and source control, combined with high-dose intravenous antibiotics including penicillin and clindamycin to inhibit toxin production and bacterial growth. Hyperbaric oxygen therapy, delivered at 3 atmospheres absolute for 90 minutes per session, complements these measures by inhibiting clostridial alpha-toxin synthesis and enhancing host defenses, with studies showing up to a 50% relative reduction in mortality when added to surgery and antibiotics. Adjunctive therapies address systemic complications like across both and bacterial etiologies, focusing on aggressive intravenous with saline to maintain urine output exceeding 200 ml per hour and prevent from . Potential pharmacological inhibitors, such as wedelolactone, have shown promise in preclinical models by reducing myotoxic damage from crotaline s through antagonism of activity, achieving over 70% inhibition of elevation, and protecting Na+,K+-ATPase with an of 0.7 μM. Following diagnosis via elevated levels, these strategies prioritize rapid intervention to mitigate progression. Emerging therapies as of 2025 offer potential alternatives or adjuncts to traditional treatments for myotoxin-induced envenoming. designed proteins have been developed to neutralize lethal toxins, including A₂ myotoxins from viper venoms, demonstrating high stability and efficacy in preclinical studies. Additionally, a phase I completed in early 2025 evaluated an oral regimen of unithiol (DMPS) for envenoming, showing safety and pharmacokinetics suitable for viper bites involving myotoxic components, potentially enabling field administration without intravenous access.

Muscle Regeneration

Repair Mechanisms

Following myotoxin-induced myonecrosis, muscle repair primarily relies on the and of satellite cells, which are Pax7-positive stem cells residing between the muscle fiber's plasma membrane and . These cells become activated early in the process, typically within the first 24 hours post-injury, in response to damage signals from the necrotic environment. Proliferation of these Pax7+ satellite cells peaks between days 3 and 5, driven by signaling pathways involving (FGF) and mechano growth factor (MGF), which promote myoblast expansion and differentiation. By day 7, myoblasts begin fusing to form myotubes, marking the onset of new fiber formation. Regenerating muscle fibers emerge as small, immature structures with central nuclei by approximately day 7, gradually increasing in size and complexity over the subsequent weeks. Full maturation, characterized by fibers approaching normal diameter and functionality, typically occurs by 28 days in experimental models using myotoxins from viperid snakes like Bothrops asper. Regeneration generally proceeds more rapidly and efficiently in fast-twitch muscles with reduced fibrosis compared to slow-twitch muscles, which regenerate more slowly yet with greater scarring. Despite these mechanisms, regeneration is frequently incomplete in severe myotoxin-induced damage, with the affected area often replaced by due to excessive deposition and fibro-adipose infiltration. This , arising from persistent and microvascular impairment, leads to long-term functional deficits such as reduced muscle strength and impaired contractility.

Influencing Factors

Several factors influence the process of muscle regeneration following myotoxin-induced damage, primarily by modulating satellite cell activation, inflammatory resolution, and (ECM) remodeling. Damage to the microvasculature often leads to ischemia and , which impair the influx of inflammatory cells necessary for debris clearance and hinder satellite cell proliferation and . Similarly, degeneration of intramuscular nerves contributes to of nascent myofibers, further compromising functional . The inflammatory response plays a pivotal role, with disruptions in macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotypes delaying myogenesis and promoting fibrosis. Regulatory T cells (Tregs), activated via the IL-33:ST2 signaling axis, enhance regeneration by secreting amphiregulin and modulating macrophage conversion, as observed in cardiotoxin-induced injury models; their depletion exacerbates repair deficits. Persistent venom components, such as those from viperid snake venoms, directly inhibit myoblast replication and myotube formation, reducing the population of MyoD-positive cells essential for repair. ECM integrity is another critical determinant, as myotoxin-associated metalloproteinases degrade collagens and , leading to disruption and excessive that impedes satellite cell migration and . Host-related factors, including age and sex hormones, also modulate outcomes; aging impairs satellite cell function and activity in cardiotoxin models, while deficiency delays regeneration, which can be rescued by supplementation. Testosterone promotes satellite cell , with males exhibiting larger regenerated fibers compared to females. Conditions like and further exacerbate regeneration deficits by altering inflammatory profiles and growth factor signaling.