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Ryanodine receptor type 1-related myopathies (RYR1-RM) are the most common class of congenital myopathies. Historically, RYR1-RM classification and diagnosis have been guided by histopathologic findings on muscle biopsy. Main histological subtypes of RYR1-RM include central core disease, multiminicore disease, core–rod myopathy, centronuclear myopathy, and congenital fiber-type disproportion. A range of RYR1-RM clinical phenotypes has also emerged more recently and includes King Denborough syndrome, RYR1 rhabdomyolysis-myalgia syndrome, atypical periodic paralysis, congenital neuromuscular disease with uniform type 1 fibers, and late-onset axial myopathy. This expansion of the RYR1-RM disease spectrum is due, in part, to implementation of next-generation sequencing methods, which include the entire RYR1 coding sequence rather than being restricted to hotspot regions. These methods enhance diagnostic capabilities, especially given historic limitations of histopathologic and clinical overlap across RYR1-RM. Both dominant and recessive modes of inheritance have been documented, with the latter typically associated with a more severe clinical phenotype. As with all congenital myopathies, no FDA-approved treatments exist to date. Here, we review histopathologic, clinical, imaging, and genetic diagnostic features of the main RYR1-RM subtypes. We also discuss the current state of treatments and focus on disease-modulating (nongenetic) therapeutic strategies under development for RYR1-RM. Finally, perspectives for future approaches to treatment development are broached.

The RYR1 gene, which encodes the sarcoplasmic reticulum calcium release channel or type 1 ryanodine receptor (RyR1) of skeletal muscle, was sequenced in 1988 and RYR1 variations that impair calcium homeostasis and increase susceptibility to malignant hyperthermia were first identified in 1991. Since then, RYR1 -related myopathies ( RYR1 -RM) have been described as rare, histopathologically and clinically heterogeneous, and slowly progressive neuromuscular disorders. RYR1 variants can lead to dysfunctional RyR1-mediated calcium release, malignant hyperthermia susceptibility, elevated oxidative stress, deleterious post-translational modifications, and decreased RyR1 expression. RYR1 -RM-affected individuals can present with delayed motor milestones, contractures, scoliosis, ophthalmoplegia, and respiratory insufficiency. Historically, RYR1 -RM-affected individuals were diagnosed based on morphologic features observed in muscle biopsies including central cores, cores and rods, central nuclei, fiber type disproportion, and multi-minicores. However, these histopathologic features are not always specific to RYR1 -RM and often change over time. As additional phenotypes were associated with RYR1 variations (including King-Denborough syndrome, exercise-induced rhabdomyolysis, lethal multiple pterygium syndrome, adult-onset distal myopathy, atypical periodic paralysis with or without myalgia, mild calf-predominant myopathy, and dusty core disease) the overlap among diagnostic categories is ever increasing. With the continuing emergence of new clinical subtypes along the RYR1 disease spectrum and reports of adult-onset phenotypes, nuanced nomenclatures have been reported ( RYR1 - [related, related congenital, congenital] myopathies). In this narrative review, we provide historical highlights of RYR1 research, accounts of the main diagnostic disease subtypes and propose RYR1 -related disorders ( RYR1 -RD) as a unified nomenclature to describe this complex and evolving disease spectrum.

Background Pathogenic variations affecting the ryanodine receptor 1 ( RYR1 ) gene may result in a variety of neuromuscular disorders, collectively known as RYR1 -related myopathies. Considered the most common form of congenital myopathy, individuals with RYR1 -related myopathies may experience skeletal muscle weakness and fatigue, as well as reduced functional capacity. This study examined the exercise capacity in individuals with RYR1 -related myopathies during a cardiopulmonary exercise test. Methods Ambulatory individuals (32 adults, 16 children) with genetically confirmed RYR1 -related myopathies performed exercise testing on a cycle ergometer and a six-minute walk test at baseline and month six (pre-intervention phase) of a randomized controlled trial (NCT02362425). Outcomes at peak exercise were compared to expected values among the adult and pediatric populations, while longitudinal changes were assessed after six months. Correlations between peak exercise outcomes and the six-minute walk test distance were also examined. Results The peak outcomes of oxygen uptake, work rate and heart rate at baseline were lower (all p  < 0.001) than expected in both adults and children. Peak oxygen uptake expressed as percent predicted was 62 ± 20% and 49 ± 24% in adults and children, respectively. No changes were observed across six months for peak exercise outcomes in either group. A moderately strong positive correlation was observed for peak work rate and six-minute walk test distance among adults (r s = 0.75, p  < 0.001) and children (r s = 0.64, p  = 0.008). Conclusion Exercise capacity is diminished in adults and children with RYR1 -related myopathies yet remains stable over six months. The six-minute walk test distance had a direct relationship to peak exercise work rate in adults and children. Exercise capacity testing may be informative for individualizing exercise regimens for persons with RYR1 -related myopathies. This study was registered with www.clinicaltrials.gov (NCT02362425) on February 12, 2015.

Background Pathogenic variations in the gene encoding the skeletal muscle ryanodine receptor (RyR1) are associated with malignant hyperthermia (MH) susceptibility, a life-threatening hypermetabolic condition and RYR1 -related myopathies ( RYR1 -RM), a spectrum of rare neuromuscular disorders. In RYR1 -RM, intracellular calcium dysregulation, post-translational modifications, and decreased protein expression lead to a heterogenous clinical presentation including proximal muscle weakness, contractures, scoliosis, respiratory insufficiency, and ophthalmoplegia. Preclinical model systems of RYR1 -RM and MH have been developed to better understand underlying pathomechanisms and test potential therapeutics. Methods We conducted a comprehensive scoping review of scientific literature pertaining to RYR1 -RM and MH preclinical model systems in accordance with the PRISMA Scoping Reviews Checklist and the framework proposed by Arksey and O’Malley. Two major electronic databases (PubMed and EMBASE) were searched without language restriction for articles and abstracts published between January 1, 1990 and July 3, 2019. Results Our search yielded 5049 publications from which 262 were included in this review. A majority of variants tested in RYR1 preclinical models were localized to established MH/central core disease (MH/CCD) hot spots. A total of 250 unique RYR1 variations were reported in human/rodent/porcine models with 95% being missense substitutions. The most frequently reported RYR1 variant was R614C/R615C (human/porcine total n  = 39), followed by Y523S/Y524S (rabbit/mouse total n  = 30), I4898T/I4897T/I4895T (human/rabbit/mouse total n  = 20), and R163C/R165C (human/mouse total n  = 18). The dyspedic mouse was utilized by 47% of publications in the rodent category and its RyR1-null (1B5) myotubes were transfected in 23% of publications in the cellular model category. In studies of transfected HEK-293 cells, 57% of RYR1 variations affected the RyR1 channel and activation core domain. A total of 15 RYR1 mutant mouse strains were identified of which ten were heterozygous, three were compound heterozygous, and a further two were knockout. Porcine, avian, zebrafish, C. elegans , canine, equine, and drosophila model systems were also reported. Conclusions Over the past 30 years, there were 262 publications on MH and RYR1 -RM preclinical model systems featuring more than 200 unique RYR1 variations tested in a broad range of species. Findings from these studies have set the foundation for therapeutic development for MH and RYR1 -RM.

Background Pathogenic variants in RYR1 cause a spectrum of rare congenital myopathies associated with intracellular calcium dysregulation. Glutathione redox imbalance has been reported in several Ryr1 disease model systems and clinical studies. NAD + and NADP are essential cofactors in cellular metabolism and redox homeostasis. NAD + deficiency has been associated with skeletal muscle bioenergetic deficits in mitochondrial myopathy and sarcopenia. Methods Using a new colorimetric assay and large control dataset ( n  = 299), we assessed redox balance (glutathione, NAD + , and NADP) in whole blood from 28 RYR1 -RM affected individuals (NCT02362425). Analyses were expanded to human skeletal muscle ( n  = 4), primary myotube cultures ( n  = 5), and whole blood and skeletal muscle specimens from Ryr1 Y524S mice. The in vitro effects of nicotinamide riboside (NR) on cellular NAD + content and mitochondrial respirometry were also tested. Results At baseline, a majority of affected individuals exhibited systemic NAD + deficiency (19/28 [68%] < 21 µM) and increased NADPH concentrations (22/26 [85%] > 1.6 µM). When compared to controls, decreased NAD + /NADH and NADP/NADPH ratios were observed in 9/28 and 23/26 individuals, respectively. In patient-derived myotube cultures ( n  = 5), NR appeared to increase cellular NAD + concentrations in a dose and time-dependent manner at 72-h only and favorably modified maximal respiration and ATP production. Average whole blood GSH/GSSG ratio was comparable between groups, and redox imbalance was not observed in Ryr1 Y524S specimens. Conclusions NAD + and NADP dyshomeostasis was identified in a subset of RYR1 -RM affected individuals. Further experiments are warranted to confirm if NAD + repletion could be an attractive therapeutic approach given the favorable outcomes reported in other neuromuscular disorders. Graphical Abstract

In a phase 1 study involving children with giant axonal neuropathy, intrathecal administration of an adeno-associated virus containing a GAN transgene resulted in some improvement in motor function scores.

Athletes may be predisposed to low vitamin D concentrations, with studies reporting a high prevalence of athletes with a vitamin D concentration below 50 nmol/L across a range of sports and geographical locations, particularly over the winter months. It is well documented that vitamin D is important for osseous health by enhancing calcium absorption at the small intestine; however, emerging research suggests that vitamin D may also benefit a plethora of extra-skeletal target tissues and systems. There is strong evidence that vitamin D is capable of regulating both innate and adaptive immune processes via binding of active vitamin D to its complementary receptor. Supplementation with vitamin D may also enhance skeletal muscle function through morphological adaptations and enhanced calcium availability during cross-bridge cycling; however, an exact mechanism of action is yet to be elucidated. Such findings have prompted research into the importance of maintaining vitamin D concentrations over wintertime and the possible physiological and immunological benefits of vitamin D supplementation in athletes. The following review critically evaluates existing literature and presents novel perspectives on how vitamin D may enhance athletic performance.

RYR1 encodes the type 1 ryanodine receptor, an intracellular calcium release channel (RyR1) on the skeletal muscle sarcoplasmic reticulum (SR). Pathogenic RYR1 variations can destabilize RyR1 leading to calcium leak causing oxidative overload and myopathy. However, the effect of RyR1 leak has not been established in individuals with RYR1 -related myopathies ( RYR1 -RM), a broad spectrum of rare neuromuscular disorders. We sought to determine whether RYR1 -RM affected individuals exhibit pathologic, leaky RyR1 and whether variant location in the channel structure can predict pathogenicity. Skeletal muscle biopsies were obtained from 17 individuals with RYR1 -RM. Mutant RyR1 from these individuals exhibited pathologic SR calcium leak and increased activity of calcium-activated proteases. The increased calcium leak and protease activity were normalized by ex-vivo treatment with S107, a RyR stabilizing Rycal molecule. Using the cryo-EM structure of RyR1 and a new dataset of > 2200 suspected RYR1 -RM affected individuals we developed a method for assigning pathogenicity probabilities to RYR1 variants based on 3D co-localization of known pathogenic variants. This study provides the rationale for a clinical trial testing Rycals in RYR1 -RM affected individuals and introduces a predictive tool for investigating the pathogenicity of RYR1 variants of uncertain significance.

Purpose Vitamin D inadequacy is a global health concern in athletes as well as the general population. Whilst the role of vitamin D in skeletal health is well defined, there remains uncertainty over whether vitamin D supplementation has an added benefit beyond bone health. Methods This randomised placebo-controlled trial in healthy male and female Gaelic footballers ( n  = 42) investigated the effect of vitamin D 3 supplementation [3000 IU (75 µg) daily for 12 weeks, via an oral spray solution] on VO 2 max which was the primary outcome measure. Secondary outcomes included skeletal muscle and lung function. Results Supplementation significantly increased total 25-hydroxyvitamin D concentrations compared to the placebo group (mean ± SD change from baseline, 36.31 ± 32.34 vs. 6.11 ± 23.93 nmol/L, respectively; P  = 0.006). At baseline, 50 and 22 % of footballers presented with vitamin D insufficiency (31–49 nmol/L) and deficiency (<30 nmol/L), respectively. Total 25-hydroxyvitamin D concentration did not significantly correlate with any measure of physical performance. Analysis of covariance (ANCOVA) models demonstrated that vitamin D supplementation over 12 weeks had no significant effect on VO 2 max ( P  = 0.375), vertical jump height ( P  = 0.797), left and right handgrip strength ( P  = 0.146 and P  = 0.266, respectively), forced vital capacity ( P  = 0.573) or forced expiratory volume at 1 s ( P  = 0.665), after adjusting for confounders. The high prevalence of vitamin D inadequacy observed in this cohort of collegiate Gaelic footballers supports the need for vitamin D supplementation during wintertime to avoid being at risk of poor bone health. Conclusions Twelve-week daily supplementation with 3000 IU (75 µg) vitamin D 3 successfully resolved deficiency but did not have any significant effect on VO 2 max, skeletal muscle or lung function.

Variants in the skeletal muscle ryanodine receptor 1 gene (RYR1) result in a spectrum of RYR1-related disorders. Presentation during infancy is typical and ranges from delayed motor milestones and proximal muscle weakness to severe respiratory impairment and ophthalmoplegia. We aimed to elucidate correlations between genotype, protein structure and clinical phenotype in this rare disease population. Genetic and clinical data from 47 affected individuals were analyzed and variants mapped to the cryo-EM RyR1 structure. Comparisons of clinical severity, motor and respiratory function and symptomatology were made according to the mode of inheritance and affected RyR1 structural domain(s). Overall, 49 RYR1 variants were identified in 47 cases (dominant/de novo, n = 35; recessive, n = 12). Three variants were previously unreported. In recessive cases, facial weakness, neonatal hypotonia, ophthalmoplegia/paresis, ptosis, and scapular winging were more frequently observed than in dominant/de novo cases (all, p < 0.05). Both dominant/de novo and recessive cases exhibited core myopathy histopathology. Clinically severe cases were typically recessive or had variants localized to the RyR1 cytosolic shell domain. Motor deficits were most apparent in the MFM-32 standing and transfers dimension, [median (IQR) 85.4 (18.8)% of maximum score] and recessive cases exhibited significantly greater overall motor function impairment compared to dominant/de novo cases [79.7 (18.8)% vs. 87.5 (17.7)% of maximum score, p = 0.03]. Variant mapping revealed patterns of clinical severity across RyR1 domains, including a structural plane of interest within the RyR1 cytosolic shell, in which 84% of variants affected the bridging solenoid. We have corroborated genotype-phenotype correlations and identified RyR1 regions that may be especially sensitive to structural modification.