Myotonic dystrophy type 1 (DM1) is characterized by RNA toxicity due to the accumulation of expanded CUG-repeats (CUGexp) that sequester splicing factors, particularly members of the Muscleblind-like (Mbnl) family. Tanner et al. conducted targeted splice sequencing to reveal the extent of RNA toxicity and the therapeutic responses to oligonucleotide therapies aimed at mitigating these effects, highlighting the need for reliable measures of target engagement (ref: Tanner doi.org/10.1093/nar/). In a related study, Otero et al. explored transcriptome alterations in the frontal cortex of individuals with DM, identifying 130 high-confidence splicing changes that predominantly occurred in the cortex, indicating a significant impact of the disease on central nervous system function (ref: Otero doi.org/10.1016/j.celrep.2020.108634/). Furthermore, Rao et al. developed an inducible mouse model expressing CUGexp RNA, demonstrating reversible cardiac disease features that affect approximately 50% of DM1 patients, underscoring the multisystemic nature of the disorder (ref: Rao doi.org/10.1172/jci.insight.143465/). Lastly, Ramirez-Martinez et al. investigated the role of the nuclear envelope protein Net39, revealing its essential function in maintaining muscle nuclear integrity and chromatin organization, with its absence leading to severe myopathy and juvenile lethality (ref: Ramirez-Martinez doi.org/10.1038/s41467-021-20987-x/).

Muscle weakness, particularly in older adults, has been linked to genetic factors, as demonstrated in a genome-wide meta-analysis by Jones et al., which identified 15 susceptibility loci associated with muscle weakness in a cohort of over 256,000 individuals aged 60 and older (ref: Jones doi.org/10.1038/s41467-021-20918-w/). This study revealed that 12 of these loci had not been previously implicated in grip strength analyses, suggesting new avenues for understanding the genetic underpinnings of muscle weakness. In another study, Auslander et al. introduced the GENDULF algorithm, which utilizes transcriptomic data to identify modifier genes that could explain clinical variability in monogenic diseases, thereby enhancing the understanding of genetic contributions to muscle disorders (ref: Auslander doi.org/10.15252/msb.20209701/). Rees et al. focused on TTN-related congenital myopathies, emphasizing the diagnostic challenges posed by the prevalence of TTN variants in control populations and the need for a comprehensive clinico-pathological approach to ascertain pathogenicity (ref: Rees doi.org/10.1007/s00401-020-02257-0/). Additionally, Ortiz-Cordero et al. investigated the therapeutic potential of NAD+ in enhancing glycosylation in FKRP-mutant myotubes, providing insights into metabolic interventions for congenital muscular dystrophies (ref: Ortiz-Cordero doi.org/10.7554/eLife.65443/).

Mitochondrial disorders present significant clinical challenges due to their complex pathophysiology and variability in clinical presentation. Sharma et al. identified circulating markers of NADH-reductive stress that correlate with the severity of mitochondrial disease, particularly focusing on the m.3243A>G mutation, which is prevalent in conditions like MELAS (ref: Sharma doi.org/10.1172/JCI136055/). This study utilized advanced proteomic and metabolomic techniques to uncover biomarkers that could refine disease characterization and therapeutic monitoring. Gucek et al. further emphasized the utility of these technologies in identifying biomarkers of mitochondrial disease pathophysiology and severity, suggesting that such markers could delineate disease-modifying targets (ref: Gucek doi.org/10.1172/JCI145158/). Chakrabarty et al. contributed to this field by demonstrating how nuclear gene mutations can influence the clinical manifestations of MELAS, highlighting the interplay between nuclear and mitochondrial genetics in disease outcomes (ref: Chakrabarty doi.org/10.1007/s00415-020-10390-9/). Lastly, Nitahara-Kasahara et al. explored the potential of dental pulp stem cells in ameliorating muscle dysfunction in Duchenne muscular dystrophy, indicating a novel therapeutic avenue that may intersect with mitochondrial dysfunction (ref: Nitahara-Kasahara doi.org/10.1186/s13287-020-02099-3/).

Inflammatory myopathies, including juvenile dermatomyositis, present diagnostic and therapeutic challenges, as highlighted by Rietveld et al., who found that anti-cytosolic 5'-nucleotidase 1A autoantibodies were absent in juvenile dermatomyositis patients, suggesting a need for further exploration of autoantibody profiles in this population (ref: Rietveld doi.org/10.1002/art.41660/). Aminzadeh et al. investigated the bioactivity of extracellular vesicles (EVs) derived from cardiac stromal cells, demonstrating that casein enhances their uptake and therapeutic potential, which could have implications for treating muscle dysfunction in inflammatory conditions (ref: Aminzadeh doi.org/10.1002/jev2.12045/). Rees et al. also contributed to understanding the complexities of myopathies by examining missense variants in TTN-related congenital myopathies, emphasizing the overlap with other myopathies and the importance of a multi-faceted diagnostic approach (ref: Rees doi.org/10.1007/s00401-020-02257-0/). Park et al. explored the role of Nogo-A in myogenesis, revealing its increased expression in muscle-related pathologies and suggesting its potential as a therapeutic target (ref: Park doi.org/10.1038/s41420-020-00384-x/).

Congenital myopathies (CM) are characterized by muscle weakness from birth, and recent studies have sought to identify effective treatment strategies. Hsu et al. demonstrated that L-Carnitine ameliorates congenital myopathy in a zebrafish model with a tropomyosin 3 mutation, suggesting a potential therapeutic avenue for CM (ref: Hsu doi.org/10.1186/s12929-020-00707-1/). Scaglioni et al. reported on the administration of the antisense oligonucleotide golodirsen in Duchenne muscular dystrophy, noting its ability to reduce pathological regeneration despite questions regarding the functionality of induced dystrophin protein (ref: Scaglioni doi.org/10.1186/s40478-020-01106-1/). Scharf et al. explored blood purification techniques using cytokine adsorbers to eliminate myoglobin in critically ill patients with severe rhabdomyolysis, reporting significant reductions in myoglobin levels, which could have implications for managing muscle-related complications (ref: Scharf doi.org/10.1186/s13054-021-03468-x/). These studies collectively highlight the ongoing search for effective treatments in congenital myopathies and related disorders.

Clinical trials in myopathies have focused on evaluating the efficacy of various therapeutic interventions. Benveniste et al. conducted a randomized, double-blind, placebo-controlled trial of sirolimus in patients with inclusion body myositis, finding no significant difference in maximal voluntary isometric knee extension strength after 12 months, indicating challenges in developing effective treatments for this condition (ref: Benveniste doi.org/10.1016/S2665-9913(20)30280-0/). In contrast, Weiss et al. identified ceramide signaling as a key contributor to the pathogenesis of VCP-associated inclusion body myopathy, suggesting that targeting this pathway may offer therapeutic benefits (ref: Weiss doi.org/10.1093/hmg/). Kramerova et al. examined the effects of myostatin inhibition in a limb-girdle muscular dystrophy model, concluding that while it promotes muscle fiber hypertrophy, it may also lead to adverse effects such as poor exercise tolerance (ref: Kramerova doi.org/10.1113/JP279943/). These findings underscore the complexity of developing effective therapies for myopathies and the need for continued research into the underlying mechanisms of these disorders.

Neuromuscular disorders often present with a range of comorbidities that complicate their management. Amburgey et al. conducted a cross-sectional study of nemaline myopathy, revealing significant clinical and genetic heterogeneity among affected individuals, which underscores the importance of understanding the natural history of the disease to inform treatment strategies (ref: Amburgey doi.org/10.1212/WNL.0000000000011458/). This study highlights the need for comprehensive assessments that consider both the neuromuscular condition and associated comorbidities. The findings suggest that tailored approaches to management may be necessary to address the diverse manifestations of nemaline myopathy and improve patient outcomes.

Recent advancements in diagnostic imaging have enhanced the understanding of myopathies and their associated complications. Kholinne et al. performed a systematic review on elbow instability in refractory lateral epicondylitis, identifying risk factors and clinical characteristics that may inform treatment options (ref: Kholinne doi.org/10.1177/0363546520980133/). Sun et al. utilized cardiac magnetic resonance imaging to phenotype myocardial involvement in idiopathic inflammatory myopathies, revealing distinct cardiac involvements that could guide clinical management (ref: Sun doi.org/10.1007/s00330-020-07448-7/). Additionally, Ollitrault et al. demonstrated that Dixon-T2WI magnetic resonance imaging outperforms conventional imaging techniques in assessing thyroid eye disease, highlighting the potential for improved diagnostic accuracy in muscle-related conditions (ref: Ollitrault doi.org/10.1007/s00330-020-07540-y/). These studies collectively emphasize the critical role of advanced imaging techniques in enhancing diagnostic precision and informing treatment strategies for myopathies.