Skeletal muscle pathology is a critical but poorly understood contributor to neuromuscular degeneration in spinal and bulbar muscular atrophy (SBMA), a CAG/polyglutamine (polyQ) expansion disorder caused by mutation in the androgen receptor (AR). Using a gene-targeted SBMA mouse model, we applied single-nucleus RNA sequencing to identify a disease-specific population of skeletal muscle myonuclei that replaced normal myonuclear subtypes. This transition was associated with dysregulation of the pathway governed by PGC-1α, a central regulator of myofiber specification and metabolic identity. PGC-1α dysfunction in SBMA muscle was age-, hormone-, and polyQ length-dependent and was partially rescued by subcutaneous delivery of AR-targeted antisense oligonucleotides. Integrated ChIP-seq and RNA-seq analyses revealed that aberrant PGC-1α activity promoted the expression of a distinct set of myofiber specification genes while downregulating those that define healthy Type IIb and Type IIx myonuclei. We propose a model in which this dysfunction arose downstream of polyQ-mediated sequestration of PGC-1α cofactors MEF2, CREB, and CBP, leading to transcriptional reprogramming and cellular dysfunction. These findings implicated PGC-1α dysregulation as a key event linking AR polyQ expansion to skeletal muscle degeneration and suggested a shared mechanism for polyQ-mediated muscle pathology across related neurodegenerative diseases.

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by a mutation in the SMN1 gene, located on chromosome 5q13. It is characterized primarily by neuronal degeneration due to a deficiency in producing full-length survival motor neuron protein (FL-SMN), which results in progressive muscle weakness with complications such as scoliosis, paralysis, and even death. This article reviews the clinical and genetic aspects of the disease, its diagnosis and classification, as well as therapeutic alternatives. In this context, it highlights the role of the molecular determination of the causal genetic variant and the copy number of the homologous SMN2 gene as the primary modifiers of the course of the disease, both for diagnosis and classification, as well as for therapeutic decision making. Recently, therapies focused on modifying the natural history of SMA by increasing FL-SMN protein production have been developed. Currently, 3 treatments are available: Spinraza (nusinersen), Zolgensma (onasemnogene abeparvovec), and Evrysdi (risdiplam). Studies performed with these drugs to confirm their safety and efficacy show favorable results; however, early diagnosis is decisive for the success of any of these therapeutic alternatives.

There is renewed interest in investigating the analgesic properties of cannabis for musculoskeletal joint pain; however, available data remain limited. This cross-sectional study was designed with the objective of evaluating patients' perceptions regarding the effect of cannabis on arthritis pain. Patients with arthritis pain presenting at one of three orthopedic clinics were asked to complete the study questionnaire. Outcomes were the perceived effect of cannabis on arthritic pain (measured using the continuous visual analog scale, with scores ranging from 0% to 100%) and association between preferences, attitudes, and barriers to the clinical use of cannabis for arthritic pain (evaluated using multivariable linear regression analyses). Sample size was also calculated using multivariable regression analysis. The study included 406 patients, including 105 (26.3%) who had already previously used cannabis for medical purposes and 63 (15.8%) who had used it during the past year. Approximately one-third of the patients who were prescribed opioids (78/256, 30.5%) had used them in the last week. On an average, patients stated that cannabis could treat 53.6% ± 2.6% of their pain (95% confidence interval = 51.1%-56.1%) and helped them replace 50.4% ± 3.2% of their analgesic medications (95% confidence interval = 47.2%-53.6%). Additionally, 88.8% of the patients (135/152) believed that cannabis would aid pain management. Individuals who had used cannabis for medical purposes (odds ratio = 7.2, 95% confidence interval = 1.6-12.8, p = 0.001) and patients reporting more severe baseline pain (β = 0.2 per point, 95% confidence interval = 0.1-0.3, p = 0.012) were more likely to report meaningful pain improvement. A quarter of the patients with arthritis already used cannabis, and many patients regarded cannabis as an effective pain treatment option. Patient preferences regarding administration and distribution, timing, and indications may help inform clinicians regarding the optimal utilization of cannabis in patients with joint and arthritis pain.

Caveolae are a highly abundant surface feature of many mammalian cells, including skeletal muscle, smooth muscle, adipocytes, and fibroblasts. Dysregulation of caveolae has been implicated in a range of diseases, including muscular dystrophies, lipodystrophies, pulmonary hypertension, and various cancers. Despite their well-established links to human disease, our molecular understanding of caveolae function at the cellular level is only now emerging. Recent advances have begun to clarify how changes in caveolar components contribute to the diverse cellular processes attributed to these specialised membrane domains. This review will highlight the latest insights into the formation of caveolae and the features of these surface domains, with particular focus on the dynamic reorganisation of caveolae in response to cellular stressors.

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease characterized by progressive muscle wasting. Objective and relevant outcome measures are needed for longitudinal follow-up and clinical trials. Quantitative MR muscle parameters in the legs are sensitive to change and related to function. However, data are limited for the upper limb, which is crucial for nonambulant DMD patients. This study investigated which MR parameters were sensitive to change over time and associated with loss of upper limb function. Muscle fat fraction (mFF) and contractile volume (CV) for elbow flexor and extensor muscles were obtained using chemical-shift-based fat-water separation scans at 3T (Philips, Ingenia) at baseline, 12, and 18 months. Standardized response means (SRM) were determined for different analysis volumes: center slice (CS), 5 (5S), 7 (7S), and all slices (AS). Parameters with SRM > 0.8 were associated with Performance of the Upper Limb, PUL2.0, using linear mixed models. Twenty nonambulant DMD patients participated. Baseline mFF ranged between 43.1% ± 12.6% for elbow extensors AS and 55.5% ± 18.9% for elbow flexors CS. SRM ranged from 0.37 for elbow flexors CV CS to 1.71 for elbow flexors AS and was consistently higher for increasing analysis volumes, longer follow-up time, and for mFF in comparison with CV. Associations with function were significant for all parameters and ranged from -0.25 to -0.34 (p < 0.001) for mFF and 0.12-0.49 (p < 0.001) for CV, except for elbow extensor CS CV (p = 0.87). Our study demonstrates that assessment of a larger part of the muscle increases the sensitivity to change over time in nonambulant DMD patients. Elbow flexor and extensor mFF 5S, 7S, and AS were sensitive to change over 12 months and related to loss of upper limb function in this population.

Genetic myopathies encompass a heterogeneous spectrum of neuromuscular disorders whose diagnosis remains challenging despite major technological advances. Traditional methods such as clinical evaluation, creatine kinase measurement, electromyography, and muscle histopathology remain valuable tools for recognizing disease patterns and, when clinically indicated, for complementing and guiding molecular investigations. However, genetically complex or atypical cases still lack an appropriate approach for assertive diagnosis. Aiming to shed light on emerging integrative molecular approaches, this review will discuss the evolving diagnostic landscape of myopathies, highlighting the integration of next-generation molecular tools with conventional methodologies for assertive diagnosis. Long-read sequencing and optical genome mapping have markedly increased diagnostic yield by enabling comprehensive detection of structural variants and complex genomic rearrangements in different myopathies. Complementary proteomic and transcriptomic analyses provide functional insight into how genetic variants alter protein expression and cellular pathways, supporting biomarker discovery and therapeutic development. Together, these omics approaches bridge the gap between genetic alterations and their functional and clinical manifestations in myopathies. They improve the interpretation of variants of uncertain significance, facilitate the identification of biomarkers linked with disease severity or therapeutic response, and support the development of personalized therapeutic strategies, advancing precision medicine in neuromuscular disorders.

Fibroblasts are critical for stabilizing skeletal muscle and facilitating wound healing after injury but become overactivated and lead to fibrotic replacement of muscle tissue in chronic degenerative diseases such as Duchenne muscular dystrophy (DMD). We have previously shown that the mineralocorticoid receptor (MR) is present in skeletal muscle and MR antagonist drugs reduce fibrosis and chronic inflammation in dystrophic mouse models. Indirect MR signaling from other cell types in the muscle microenvironment affects fibroblast gene expression and function. However, the direct effects of MR activation of skeletal muscle fibroblasts are unknown.