ryanodine and Muscle-Weakness

The core myopathies are a group of congenital myopathies with variable clinical expression - ranging from early-onset skeletal-muscle weakness to later-onset disease of variable severity - that are identified by characteristic 'core-like' lesions in myofibers and the presence of hypothonia and slowly or rather non-progressive muscle weakness. The genetic causes are diverse; central core disease is most often caused by mutations in ryanodine receptor 1 (

Topics: Alkaloids; Animals; Connectin; Disease Models, Animal; Disease Progression; Gene Expression Regulation; Genetic Association Studies; Genetic Variation; HEK293 Cells; Humans; Male; Mice; Mice, Transgenic; Muscle Proteins; Muscle Weakness; Muscle, Skeletal; Myopathies, Structural, Congenital; Myopathy, Central Core; Ophthalmoplegia; Protein Kinases; Ryanodine; Ryanodine Receptor Calcium Release Channel; Selenoproteins

Skeletal muscle weakness is a reported ailment in individuals working in commercial hog confinement facilities. To date, specific mechanisms responsible for this symptom remain undefined. The purpose of this study was to assess whether hog barn dust (HBD) contains components that are capable of binding to and modulating the activity of type 1 ryanodine receptor Ca2+-release channel (RyR1), a key regulator of skeletal muscle function. HBD collected from confinement facilities in Nebraska were extracted with chloroform, filtered, and rotary evaporated to dryness. Residues were resuspended in hexane-chloroform (20:1) and precipitates, referred to as HBDorg, were air-dried and studied further. In competition assays, HBDorg dose-dependently displaced [3H]ryanodine from binding sites on RyR1 with an IC50 of 1.5±0.1 microg/ml (Ki=0.4±0.0 microg/ml). In single-channel assays using RyR1 reconstituted into a lipid bilayer, HBDorg exhibited three distinct dose-dependent effects: first it increased the open probability of RyR1 by increasing its gating frequency and dwell time in the open state, then it induced a state of reduced conductance (55% of maximum) that was more likely to occur and persist at positive holding potentials, and finally it irreversibly closed RyR1. In differentiated C2C12 myotubes, addition of HBD triggered a rise in intracellular Ca2+ that was blocked by pretreatment with ryanodine. Since persistent activation and/or closure of RyR1 results in skeletal muscle weakness, these new data suggest that HBD is responsible, at least in part, for the muscle ailment reported by hog confinement workers.

Topics: Agricultural Workers' Diseases; Animals; Binding Sites; Binding, Competitive; Calcium; Calcium Channel Agonists; Calcium Channel Blockers; Cell Line; Chloroform; Chromatography, Thin Layer; Dose-Response Relationship, Drug; Dust; Housing, Animal; Humans; Ion Channel Gating; Membrane Potentials; Mice; Muscle Fibers, Skeletal; Muscle Weakness; Muscle, Skeletal; Occupational Health; Rabbits; Risk Assessment; Ryanodine; Ryanodine Receptor Calcium Release Channel; Solvents; Sus scrofa