Myopathies represent a highly heterogeneous group of skeletal muscle disorders characterized clinically by debilitating muscle weakness, exertional fatigue, and diminished physical capacity [1,2]. These conditions emerge from diverse etiologies, encompassing genetic mutations, metabolic derangements, inflammatory cascades, and exposure to specific pharmacological agents or toxins. Unlike neuropathic disorders, which stem from lesions within the nervous system, myopathies originate intrinsically within the muscle fibers, leading to direct structural and functional impairment [3,4]. Normal skeletal muscle function is biochemically dependent on the precise, coordinated regulation of multiple cellular processes, notably energy production, calcium signaling, and redox homeostasis [5–7]. To sustain contractile activity, skeletal muscle demands a relentless supply of ATP, synthesized via interconnected pathways such as glycolysis, fatty acid oxidation, and mitochondrial oxidative phosphorylation. The disruption of these bioenergetic pathways directly triggers energy deficiency, compromised contraction, and heightened vulnerability to load-induced muscle damage [8,9]. Furthermore, the loss of intracellular calcium regulation and the unregulated productions of reactive oxygen species (ROS) significantly drive the degenerative process.

Clinically, myopathies are broadly classified into inherited (primary) and acquired (secondary) etiologies. Genetic variants such as muscular dystrophies, congenital myopathies, and metabolic myopathies are driven by discrete molecular anomalies that affect structural integrity, energy metabolism, or contractile mechanics, ultimately triggering systemic muscle wasting and functional decline [10,11]. For instance, Duchenne and Becker muscular dystrophies are intrinsically linked to mutations in the dystrophin gene, which potentially lead to a deficiency in the dystrophin protein and subsequent muscle wasting [12,13]. Conversely, metabolic myopathies emerge from specific enzymatic defects within bioenergetic cascades, including glycogen storage diseases, fatty acid oxidation disorders, and mitochondrial myopathies [14]. Acquired myopathies predominantly result from immune-mediated tissue damage, endocrine dysfunction, or infectious insults that compromise muscle metabolism and integrity [15,16].

The underlying pathophysiology of these myopathies is fundamentally linked to localized biochemical failures. Proteostasis imbalance and the dysfunction of structural proteins, like dystrophin, compromise sarcolemma stability, rendering fibers highly susceptible to contraction-induced injury [17,18]. Energy metabolism defects severely limit ATP availability by impairing glycogenolysis and disrupting fatty acid oxidation, thereby starving the muscle during prolonged exertion [19,20]. Compounding these energy deficits is a marked elevation in oxidative stress, where excessive ROS accumulation inflicts lipid peroxidation, protein oxidation, and DNA damage, thereby overwhelming intrinsic antioxidant defenses and exacerbating cellular injury [21]. Concurrently, the dysregulation of calcium homeostasis via sarcoplasmic reticulum dysfunction, promotes pathological intracellular calcium accumulation, which aberrantly activates destructive proteases and accelerates muscle fiber necrosis [22–24].

The pathogenic mechanisms of myopathies are basically rooted in genetic mutations that weaken muscle fiber architecture and metabolic capacity [25]. These abnormalities can manifest in both nuclear and mitochondrial genomes across varying inheritance patterns. Beyond primary sequence mutations, disease pathogenesis is heavily influenced by transcriptional and translational defects, including altered mRNA stability, aberrant splicing events, and translational inefficiencies that yield truncated or non-functional proteins [26,27]. RNA processing errors, such as alternative splicing defects, are now recognized as central to the etiology of several myopathies involving sarcomeric and cytoskeletal networks [28,29].

Epigenetic modifications also exert profound regulatory control over muscle cell expression profiles. Dysregulated DNA methylation, aberrant histone modifications, and chromatin remodeling can severely impair the transcriptional networks governing muscle differentiation, regeneration, and metabolic adaptation, thereby propelling disease progression under stress conditions [30,31]. Additionally, mitochondrial genetics is crucial, as mutations in mitochondrial DNA disrupt the cell's energy production, leading to decreased ATP synthesis and increased cellular damage from oxidative stress [32]. Because skeletal muscle possesses massive bioenergetic demands, these mitochondrial defects clearly highlight the interplay between genomic integrity and bioenergetics in myopathic disease.

Skeletal muscle degeneration in myopathies stems from the dysregulation of interconnected cell death and clearance pathways [33]. Because skeletal muscle possesses high metabolic requirements and limited regenerative capacity, it is exquisitely sensitive to disturbances in these networks. Apoptosis, which is heavily driven by intrinsic mitochondrial dysfunction and oxidative stress, triggers caspase-dependent cell death, thereby inducing the loss of myonuclei and the structural collapse of individual fibers. This apoptotic signaling is prominently activated in Duchenne muscular dystrophy and inflammatory myopathies, where mitochondrial damage is amplified by immune-mediated stress (Figure 1) [34].

Figure 1. Interconnected cell death and clearance networks in myopathic skeletal muscle.

Conversely, necrosis represents an uncontrolled, cytolytic cell death pathway characterized by the rupture of the sarcolemma [35,36]. In muscular dystrophies, mechanical stress placed on structurally deficient membranes initiates necrosis, inciting a cascade of local inflammation and subsequent fibrosis that ultimately replaces functional muscle tissue. Furthermore, impaired autophagy, a process responsible for the degradation and recycling of damaged organelles, contributes significantly to cellular toxicity. Defective autophagic flux promotes the toxic accumulation of misfolded proteins and dysfunctional mitochondria, a hallmark of inclusion body myositis and other degenerative conditions [37]. Importantly, these pathways are not mutually exclusive but operate dynamically; autophagic failure can readily shift a stressed muscle cell toward apoptotic or necrotic cell death, making these interconnected networks vital therapeutic targets.

Existing clinical practices for muscular myopathies focus on biochemical remediation that are aimed at stabilizing muscle architecture while attempting to correct underlying metabolic deficits. Corticosteroids remain the cornerstone of traditional pharmacological intervention, due to their ability to delay the progression of disease by suppressing chronic inflammation and stabilizing the sarcolemma [38,39]. However, their long-term utility is significantly undermined by systemic toxicities, most notably steroid-induced muscle atrophy, which can paradoxically exacerbate physical decline. Consequently, current literature categorizes these traditional therapies, including metabolic supplements like creatine and carnitine as primarily symptomatic or supportive, as they often yield modest and variable clinical outcomes without addressing the primary genetic drivers of degeneration.

The most transformative advancements in management currently reside within the realm of gene and molecular therapy. Adeno-associated virus (AAV)-mediated gene replacement and antisense oligonucleotide-driven exon skipping have demonstrated the capacity to restore partial protein expression, such as dystrophin, thereby stabilizing the sarcolemma and slowing myofiber breakdown [40,41]. Furthermore, CRISPR/Cas9 genome editing holds the ultimate promise of permanent mutational correction at the genomic level [43]. While these technologies represent a shift toward definitive disease modification, their clinical application remains challenged by delivery inefficiencies, potential off-target toxicities, and the complexities of achieving systemic therapeutic reach.

Consequently, the field is rapidly transitioning toward the molecular reprogramming of muscle tissue, targeting upstream regulatory networks to counteract downstream pathology. MicroRNA (miRNA) modulation, specifically targeting muscle-specific transcripts like miR-1 and miR-206, has shown the ability to restore differentiation and blunt fibrotic pathways [44]. Parallel epigenetic interventions, such as histone deacetylase (HDAC) inhibitors, seek to reawaken regenerative transcriptional programs within satellite cells to promote endogenous myogenic repair. By manipulating major metabolic nodes such as inhibiting myostatin or modulating the AMPK/mTOR axis, researchers aim to shift the cellular phenotype from a state of chronic degeneration toward one of hypertrophy and enhanced autophagic clearance (Figure 2) [45].

Figure 2. Evolution of therapeutic remediation strategies for myopathies.

The integration of these advanced therapeutics is the cornerstone of Precision Medicine, a model that designs targeted interventions based on an individual's unique genetic and metabolic architecture. Because shared biological pathways (e.g., calcium dysregulation) can arise from vastly different genetic mutations, generalized treatments often yield suboptimal efficacy or unintended toxicity. By utilizing multi-omics platforms and artificial intelligence, precision medicine allows for précised stratification of disease and optimized pharmacogenomic responses [46,47].

However, the rapid acceleration of these high-cost, highly technical interventions poses a severe risk of widening global health disparities. While well-resourced healthcare systems readily integrate viral vector therapies and NGS diagnostics, low- and middle-income regions, particularly across Africa face profound structural barriers, including insufficient diagnostic infrastructure and prohibitive costs [48]. Without deliberate international policy frameworks focusing on capacity building, equitable pricing, and technology transfer, the gains of genomic medicine will remain inaccessible to a vast portion of the global population, thereby reinforcing existing inequities [49]. Global accessibility therefore must be embedded as a core scientific objective during the early phases of therapeutic research.

Myopathies constitute a multifaceted array of skeletal muscle disorders driven by intersecting genetic, metabolic, and cellular disturbances. The inexorable progression of muscle dysfunction is biochemically rooted to the disruption of energy metabolism, excessive oxidative stress, and the critical failure of calcium homeostasis. While molecular biology has unravelled the complex pathogenic mechanisms and ushered in an era of precision therapeutics that range from gene editing to epigenetic reprogramming, significant technical and systemic challenges remain. Moving forward, the successful remediation of myopathies will demand an integrated, multi-omics approaches that move beyond single-target therapies. Equally critical is the necessity to harmonize these sophisticated scientific advancements with equitable global healthcare frameworks, ensuring that precision medicine delivers transformative clinical benefits to all affected populations, regardless of geographic or socioeconomic boundaries.