Integrative Approaches to Myopathies and Muscular Dystrophies: Molecular Mechanisms, Diagnostics, and Future Therapies

Abstract

Myopathies and muscular dystrophies are a diverse group of rare or ultra-rare diseases that significantly impact patients' quality of life and pose major challenges for diagnosis and treatment. Despite their heterogeneity, many share common molecular mechanisms, particularly involving sarcomeric dysfunction, impaired autophagy, and disrupted gene expression. This review explores the genetic and pathophysiological foundations of major myopathy subtypes, including cardiomyopathies, metabolic and mitochondrial myopathies, congenital and distal myopathies, myofibrillar myopathies, inflammatory myopathies, and muscular dystrophies. Special emphasis is placed on the role of autophagy dysregulation in disease progression, as well as its therapeutic potential. We discuss emerging diagnostic approaches, such as whole-exome sequencing, advanced imaging, and muscle biopsy, alongside therapeutic strategies, including physiotherapy, supplementation, autophagy modulators, and gene therapies. Gene therapy methods, such as adeno-associated virus (AAV) vectors, CRISPR-Cas9, and antisense oligonucleotide, are evaluated for their promise and limitations. The review also highlights the potential of drug repurposing and artificial intelligence tools in advancing diagnostics and personalized treatment. By identifying shared molecular targets, particularly in autophagy and proteostasis networks, we propose unified therapeutic strategies across multiple myopathy subtypes. Finally, we discuss international research collaborations and rare disease programs that are driving innovation in this evolving field.

Keywords: drug repositioning; gene therapy; muscular diseases; myopathies; protein quality control.

Figure 4

During stress conditions, cells prioritize degradation by autophagy rather than proteasomes. BAG3, by having a higher affinity for Hsp-70 than BAG1, creates a complex with heat shock proteins and cargo proteins guided for degradation. A protein designated for degradation is previously ubiquitinated and binds with p62 complex with WT BAG3 releasing cargo protein upon contact with LC3-II, thus creating autophagosome which reacts with lysosome making autolysosome; meanwhile, BAG3 is guided for proteasomal degradation after successful cargo guidance. Cells presenting P209L BAG3 mutation cannot release cargo protein, because of Hsp-70s toxic gain of function in this complex, resulting in whole complex entrapment and formation of aggregates [138,143,152,153,154,155,156]. Created in BioRender. Rintz, E. (2025) https://BioRender.com/ahsr8iq.

Figure 1

The main classification of myopathies: (a) inherited myopathies, (b) acquired myopathies, and (c) muscular dystrophies; yellow borders point out described in this article. Created in BioRender. Rintz, E. (2025) (a) https://BioRender.com/5pub3bg; (b) https://BioRender.com/xkfzqrb; (c) https://BioRender.com/702uwk4.

Figure 2

Potential molecular pathway for dilated cardiomyopathy development. Increasing mechanical stress leads to elevated levels of angiotensin II, which stimulates the G-protein-coupled receptor. The α-subunit of this receptor activates phospholipase C, which breaks down PIP2 into IP3. IP3 stimulates the release of calcium into the cytoplasm. When Ca²⁺ binds to calmodulin, calcineurin is activated, which in turn, activates the transcription factors MEF2 and NFAT. The β and γ subunits of the GPCR also activate signaling pathways through the activation of PI3Kγ, which converts PIP2 into PIP3. This leads to the activation of substrates required for the formation of PDK1, which phosphorylates Akt and thereby inhibits GSK-3β. As a result, NFAT is not deactivated by phosphorylation and is transported into the nucleus, enhancing cardiac hypertrophy. The previously formed PIP3 also activates NADPH oxidase, contributing to increased levels of ROS and activation of the MAPK pathway through phosphorylation of the p38, ERK1/2, and JNK1/2 subunits, which stimulate the expression of genes responsible for hypertrophy. Mechanical stress can also lead to cell death by increasing TNFα levels, which, through interaction with the FAS receptor, activates Caspase 8, as well as through mitochondrial membrane damage and apoptosome activation. Created in BioRender. Rintz, E. (2025) https://BioRender.com/bhc02ja.

Figure 3

(A) Schematic representation of glycogen metabolism in muscle cells including selected enzymatic defects in GSD. Glucose supplied by the GLUT transporter 4, is phosphorylated in the cytoplasm to form Glucose-6-phosphate (glucose 6-P) and then converted to glucose-1-phosphate (glucose 1-P). Glucose 1-P serves to synthesize UDP-glucose, which is the direct donor of glucose residues in glycogenesis. UDP-glucose is incorporated into the structure of glycogen, which is the spare form of glucose in muscle. In the process of glycogenolysis, glycogen is degraded by glycogen phosphorylase (phosphorylase a and its inactive form, phosphorylase b), leading to the formation of dextrins; the lack of glycogen phosphorylase leads to GSD V. Dextrins are then branched leading to the formation of glucose 1-P by debanching enzyme; its absence will result in GSD III. (B) In response to increased pH levels in the lysosome due to glycogen accumulation, V-ATPase activity increases. V-ATPase is crucial for maintaining the Ragulator-Rags complex on lysosomes, which in turn bound to GTP attracts and localizes mTORC1 to the surface of lysosomes. Once mTORC1 is located, Rheb-GTP activates the kinase. This causes mTORC1 to be attached to lysosomes during both starvation and nutrient sufficiency. It does not function properly in either situation—during starvation, mTOR is not fully activated. Despite the presence of inhibitors (AMPK and TSC2 complex) on lysosomes, the continuous proximity of Rheb counteracts full mTOR deactivation. This results in lysosome distortion and dysfunction of the t-SNARE protein, preventing proper fusion of the autophagosome with the lysosome and delivery of glycogen to the lysosome. (C) Schematic analysis of mitochondrial fatty acid β-oxidation. Long-chain, medium-chain, and short-chain acyl-CoA (LC-A CoA, MC-A CoA, SC-A CoA) are oxidized by the respective dehydrogenases: VLCAD/LCAD (very/long-chain acyl-CoA dehydrogenase) and MCAD. (D) Mitochondrial DNA (mtDNA) metabolism and effects of specific mutations. Created in BioRender. Rintz, E. (2025) https://BioRender.com/519h7hq.

Figure 5

Molecular events present in the GNE myopathy. Abnormal GM3 and GD3 lead to Aβ synthesis disorder in the Golgi apparatus and endoplasmic reticulum of GNE. At the same time, hyposialylated NEP cannot clear Aβ. Aβ deposition generates ER stress in GNE-mutant cells, which further triggers survival or apoptotic signaling mediated by IRE1-α or PERK, respectively. Molecular chaperones, ERAD and UPS, are all involved in the clearance of misfolded proteins. In the case of Aβ deposition, the autophagy–lysosome pathway is activated immediately to correct or degrade Aβ. Many molecules related to apoptosis in GNE myopathy, such as caspase 3 and IGF-1R, control cell survival and apoptosis by regulating the balance between AKT and ERK. Increased presence of autophagy markers, such as p62, LC3, and lysosome membrane-associated proteins (LAMP1 and LAMP2), were detected in patients’ muscle biopsies. Created in BioRender. Rintz, E. (2025) https://BioRender.com/8v71k21.

Figure 6

Molecular mechanism of muscular dystrophies. (A) Molecular mechanism of Duchenne Muscular Dystrophy. (B) Molecular mechanism of Facioscapulohumeral Dystrophy (C) Molecular mechanism of Myotonic Dystrophies Type 1 and Type 2. See details in full text. Created in BioRender. Rintz, E. (2025) (A) https://BioRender.com/mo27ly5; (B) https://BioRender.com/jsm1r9g; (C) https://BioRender.com/lmmi6fw.

Figure 7

Examples of relationships between main types of myopathies, muscular dystrophies, and autophagy. Arrows—one myopathy or particular process causes another. Created in BioRender. Rintz, E. (2025) https://BioRender.com/80fk48r.