FSHD is among the most common hereditary neuromuscular disorders, affecting roughly 5 in 100,000 people worldwide. Unlike Duchenne muscular dystrophy, it does not shorten life expectancy, but its progressive nature exacts a heavy toll. The disease stems from a genetic error on chromosome 4: a contraction of D4Z4 macrosatellite repeats causes hypomethylation of the region, allowing sporadic expression of DUX4, a transcription factor normally silent in mature skeletal muscle. DUX4 switches on germline and early stem cell genes that should never be active in adult muscle, disrupting cellular homeostasis and triggering inflammation and apoptosis. The result is a progressive, asymmetric loss of muscle mass that typically begins in the face, shoulder girdle, and upper arms, later spreading to the trunk and lower limbs. Severity varies enormously: up to 30 percent of genetic carriers report no symptoms, while approximately 20 percent become wheelchair-dependent.

The pathological picture is more complex than simple muscle wasting. Quantitative MRI reveals fatty infiltration two to three times greater than in age-matched controls, along with STIR hyperintensity lesions—pockets of edema interpreted as signs of active inflammation. Muscle biopsies from STIR-positive regions show mononuclear cell infiltrates, elevated expression of major histocompatibility complex I, and greater collagen deposition, indicating fibrosis. Oxidative stress compounds the damage: transcriptomic analyses show upregulation of TNFα pathway genes, FSHD myoblasts display increased susceptibility to oxidative injury, and patients carry a reduced ratio of reduced to oxidized glutathione in their blood. Critically, these radiological features—fatty infiltration, lesion burden, and shrinking muscle volume—are the most sensitive markers of progression, detectable within a single year, while functional scores often lag behind.

Weakness in FSHD exceeds what muscle loss alone can explain. Individuals consistently show reductions in maximal voluntary contraction force of more than 40 percent compared with controls, and even after correcting for fatty infiltration, specific force—the force per unit of contractile cross-sectional area—remains reduced by over 30 percent. Yet isolated single muscle fibers from the same patients generate nearly normal specific force. This paradox points the finger away from the contractile machinery itself and toward collective impairments: MRI-based estimates of contractile area likely overstate true fiber area because they cannot distinguish fibrosis, edema, and interstitial cells from contractile tissue. Emerging evidence also implicates defective excitation–contraction coupling. Meta-analyses reveal downregulation of genes associated with neuromuscular junction architecture, single-fiber electromyography shows abnormal transmission correlated with disease duration, sarcolemmal reorganization increases the distance between the sarcolemma and the nearest myofibril—potentially disrupting the T-tubule network—and muscle excitability studies reveal partial depolarization of the resting membrane potential, which could inactivate voltage-gated sodium channels and attenuate calcium release from the sarcoplasmic reticulum.

Against this backdrop, the review defines high-load resistance training precisely: programs using loads of 70 to 90 percent of one-repetition maximum, or the 4 to 12 repetition maximum range, which meta-analyses show are most effective at simultaneously increasing muscle mass and maximal strength. The authors emphasize that while lighter loads produce comparable hypertrophy when volume is matched, higher loads yield greater strength gains. Optimal prescription involves at least four sets per muscle group per week—ideally ten or more for maximizing hypertrophy—rest intervals of one to two minutes between sets, a minimum frequency of two weekly bouts, and progressive overload, in which loads are increased over time to maintain the targeted repetition range at near-maximal effort.

The acute responses to such training are well characterized in healthy populations. A single bout causes rapid neuromuscular fatigue, myofibrillar disruption visible under electron microscopy, mild swelling lasting up to 48 hours, soreness persisting for days, and elevated serum creatine kinase. Plasma cytokines such as IL-6, IL-1ra, MCP-1, and G-CSF rise transiently, and severe disruption is followed by mononuclear cell infiltration—collectively termed exercise-induced muscle damage. Crucially, these responses are normal remodeling processes, not signs of intolerance. Healthy individuals recover within days and are protected against comparable damage in subsequent bouts, a phenomenon known as the repeated bout effect. Meanwhile, anabolic signaling through MAPK pathways and mTORC1 drives muscle protein synthesis that remains elevated beyond 48 hours, while protein degradation returns to baseline—the cumulative imbalance producing net accretion of contractile protein.

Long-term, the benefits are substantial. Twelve to 24 weeks of high-load resistance training typically increases one-repetition maximum by 20 to 50 percent, with early gains driven primarily by neural adaptations—increased motor unit recruitment and discharge rate within the first two to four weeks—before morphological hypertrophy of roughly 5 to 20 percent becomes detectable. Strength gains translate into improved gait speed, chair stand performance, and balance, the very capacities that underpin independence. Equally relevant to FSHD, evidence from other populations shows that resistance training reduces fatty infiltration in older and overweight adults, attenuates chronic low-grade inflammation as measured by C-reactive protein, reduces oxidative stress markers in metabolic conditions, and—strikingly—alters inflammatory gene expression and reduces interstitial fibrosis in myositis, an autoimmune myopathy that shares mononuclear infiltration, fatty infiltration, fibrosis, and muscle fiber regeneration with FSHD.

So where did the caution come from? The review traces much of the dogma to two influential studies. Over 50 years ago, Johnson and Braddom reported that most members of an FSHD family were weaker in their dominant arm—the one used habitually—and concluded that extensive use, including resistance training, accelerates disease progression. But the conclusions were never substantiated by statistical analysis, and the methods were described only vaguely. Brouwer and colleagues later found statistically significant side-to-side differences in just 3 of 10 strength tests, with small numerical differences relative to large standard deviations. Subsequent studies across 102 individuals with FSHD found no effect of handedness on weakness patterns, and a case report in monozygotic twins reached the same conclusion. The overwork weakness hypothesis, in other words, does not withstand replication.

The recommendation to avoid loads above 30 percent of one-repetition maximum fares no better. Several resistance training studies have included individuals with FSHD who repeatedly lifted loads well above that threshold, and all reported the training was well tolerated, with most showing moderate improvements in strength and function. On eccentric contractions, the review notes that submaximal eccentric actions—inevitable in daily activities like sitting down—are demonstrably safe, and the only study to test maximal eccentric contractions found that individuals with myopathic disease showed slightly attenuated signs of exercise-induced muscle damage compared with healthy controls, whose creatine kinase rose significantly more three days post-exercise. Though limited to two individuals with FSHD, the study gives no indication of heightened vulnerability. Persistent soreness, the authors add, is the expected response of any untrained person beginning training—not evidence of disease provocation—and clinicians should avoid language that reinforces a sense of fragility, which fuels fear and exercise avoidance.

The most cited study on the topic, published by van der Kooi and colleagues in 2004, trained 19 individuals with FSHD for 52 weeks and is frequently invoked as proof that resistance training offers no benefit. Yet the review highlights critical limitations: the program started with 10RM loads progressing toward 5RM—below the high-load definition—lacked a healthy positive control group, and produced a 37 percent increase in elbow flexion one-repetition maximum that has been overshadowed by emphasis on its negative findings. No available study has adequately addressed whether high-load training affects the major pathological features of FSHD, considered the disease’s inherent asymmetry, or employed gold-standard whole-body MRI to track fibrosis, fatty infiltration, and muscle mass. Until such trials are conducted, the authors conclude, patients and clinicians will remain without answers about an intervention that is accessible, inexpensive, and likely low-risk—one that could delay the mobility decline and loss of independence that define advanced FSHD.

Subject of Research: FSHD

Article Title: High-load resistance training and FSHD: harmful mixture or a silver bullet combination?

Article References: Meinhold, M., & Hornberger, T. A. (2026). High-load resistance training and FSHD: harmful mixture or a silver bullet combination?. Journal of Neurology, 273(10), Article 605. https://doi.org/10.1007/s00415-026-14148-7

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14148-7

Keywords: FSHD, resistance training, muscular dystrophy, exercise science, neuromuscular disorders, DUX4, muscle physiology, High-load, resistance, training, harmful, mixture

The genetic roots of FSHD lie in a region of chromosome 4 called D4Z4, a stretch of repeated DNA sequences that normally keeps a gene called DUX4 silenced. In FSHD1, which accounts for about 95 percent of cases, these repeats contract to between one and ten units instead of the usual eleven or more, allowing DUX4 to be aberrantly expressed in muscle tissue. DUX4 is a transcription factor that wreaks havoc once activated, driving oxidative stress, impaired muscle regeneration, and the activation of innate immune and antiviral pathways. The shorter the residual repeat array, the more DUX4 is released and, generally, the earlier and more severe the disease. But this relationship is far from complete. Even relatives carrying identical D4Z4 contractions can differ dramatically in severity, a gap that has long suggested the involvement of additional modifiers, whether genetic, epigenetic, environmental, or immunological.

That immunology might matter in FSHD is not an entirely new idea. Muscle biopsies from patients frequently show inflammatory infiltrates dominated by CD8-positive T lymphocytes and macrophages, and magnetic resonance imaging reveals muscle edema during active phases of the disease. Transcriptomic studies have documented upregulation of interferon signaling and cytokine-related genes in FSHD tissues, and DUX4 itself can induce the expression of inflammatory mediators. Isolated case reports have also described patients with both FSHD and autoimmune conditions such as myasthenia gravis or inflammatory myopathies. What remained unknown was whether these co-occurrences were coincidental or whether autoimmune disease systematically shapes the course of the muscular dystrophy.

To answer that question, the Nice team analyzed 299 adults with genetically confirmed FSHD1, all evaluated between 2017 and 2025, for whom complete demographic, clinical, and genetic data were available. Each patient was classified using the Comprehensive Clinical Evaluation Form, a standardized tool that sorts patients into four categories: category A for the typical facial and scapular phenotype, category B for incomplete weakness limited to the scapular or facial muscles, category C for pauci-symptomatic or asymptomatic carriers, and category D for atypical presentations. Autoimmune diagnoses were only accepted when confirmed by the relevant specialist, with strict criteria applied for conditions such as Sjögren’s syndrome, which required fulfillment of the 2016 ACR/EULAR classification criteria with positive anti-SSA or anti-SSB antibodies.

The results were striking. Eighty-two patients, or 27.4 percent of the cohort, had at least one autoimmune disease, and fourteen of them carried two. In total, 96 autoimmune conditions spanning fourteen distinct diagnoses were recorded. Hashimoto’s thyroiditis was the most common, affecting 32 patients, followed by autoimmune diabetes in 16, atopic dermatitis in 12, myasthenia gravis in 10, and primary biliary cholangitis and psoriasis in 7 each. When the researchers compared these counts with published prevalence estimates from the general population, several conditions stood out as dramatically overrepresented. Myasthenia gravis appeared roughly 167 times more often than expected, primary biliary cholangitis about 106 times, autoimmune diabetes nearly 43 times, idiopathic inflammatory myositis about 72 times, and Sjögren’s syndrome more than 16 times. By contrast, common inflammatory skin disorders such as atopic dermatitis and psoriasis were not enriched, suggesting that the association involves specific autoimmune mechanisms rather than a generalized tendency toward inflammation.

The clinical implications were equally compelling. Patients with autoimmune comorbidities were older at examination, with a mean age of 56.3 years compared with 51.2 years, and had a later disease onset, at 38.4 years versus 33.7 years. More intriguingly, despite carrying significantly larger D4Z4 repeat arrays, 7.18 repeat units on average versus 6.53, which should ordinarily predict a milder disease, these patients scored significantly worse on the FSHD severity scale, 7.98 versus 6.56. The distribution of phenotypes also shifted: autoimmune patients were far more likely to fall into category D, the atypical group, at 30.5 percent versus 8.3 percent of non-autoimmune patients, and less likely to show the classical category A presentation. Within categories A and B, autoimmune patients again had significantly higher severity scores.

To test whether autoimmunity was an independent driver of severity rather than a byproduct of age or genetic background, the researchers built a multivariable linear regression model incorporating age, sex, disease duration, D4Z4 repeat number, and autoimmune status. The genetic effect held firm: each additional repeat unit was associated with a decrease in severity score of nearly one point, with a beta coefficient of minus 0.96, while each additional year of disease duration added 0.11 points. But the autoimmune signal was even more pronounced. After adjusting for every other variable, the presence of an autoimmune disease added an average of 2.12 points to the severity score, an effect that was highly statistically significant. Notably, there was no interaction between autoimmune status and repeat number, meaning the autoimmune penalty appeared to operate in parallel with, rather than through, the primary genetic defect.

Perhaps the most provocative finding concerns the subgroup of patients carrying seven to ten D4Z4 repeat units, the larger residual arrays conventionally associated with milder disease. Autoimmune disease was substantially more frequent in this group, affecting 36.1 percent of patients with seven to ten repeats compared with just 16.2 percent of those with shorter alleles, and 73 of the 96 recorded autoimmune conditions occurred in the larger-repeat subgroup. The authors propose a conceptual model in which the relative contribution of disease modifiers depends on repeat size. In patients with short alleles, below seven repeats, the primary genetic contraction dominates the clinical picture. In those with larger alleles, however, secondary factors, including autoimmune disease, unrelated genetic disorders, hormones, telomere shortening, aging, and immunosenescence, may play a proportionally greater role in shaping phenotype and severity. This could explain why patients with seemingly mild genetics sometimes develop serious disease, and why the seven-to-ten repeat range appears repeatedly as a hotspot for modifier effects in this and previous studies from the same group.

The biological mechanisms linking autoimmunity and FSHD severity remain speculative but plausible. Chronic muscle injury in FSHD may release intracellular antigens and pro-inflammatory mediators that fuel immune activation, while systemic autoimmune inflammation could in turn exacerbate muscle dysfunction, impair regeneration, or interact with the epigenetic regulation of the D4Z4 locus itself. The later disease onset observed in autoimmune patients hints that an age-related pro-inflammatory state, compounded by immunosenescence, may gradually tip the balance in genetically susceptible individuals. The authors are careful to note that their study is retrospective and single-center, that referral bias may have inflated the detection of autoimmune comorbidities in a national neuromuscular center, and that several rare conditions were represented by too few cases for firm conclusions. Still, the message for clinical practice is clear: systematically screening FSHD patients for autoimmune disease could refine prognosis and, if future longitudinal studies confirm causality, open the door to immune-targeted therapies for a subgroup of patients whose disease severity is being quietly amplified by their own immune systems.

Subject of Research: The association between autoimmune comorbidities and clinical severity in facioscapulohumeral muscular dystrophy type 1

Article Title: Autoimmune Comorbidities as Modifiers of Phenotypic Heterogeneity in Facioscapulohumeral Dystrophy

Article References: Pini, J., Tammam, G., Ezaru, A., Gambella, M., Sanson, B., Villa, L., Cavalli, M., Ioncea, M.-B., Puma, A., & Sacconi, S. (2026). Autoimmune Comorbidities as Modifiers of Phenotypic Heterogeneity in Facioscapulohumeral Dystrophy. Annals of Clinical and Translational Neurology, Article acn3.70529. https://doi.org/10.1002/acn3.70529

Image Credits: AI Generated

DOI: 10.1002/acn3.70529

Keywords: FSHD, muscular dystrophy, autoimmune disease, DUX4, D4Z4, myasthenia gravis, Hashimoto's thyroiditis, disease modifiers, genetics, inflammation, clinical severity, neuromuscular disorders