Disturbances in calcium homeostasis in skeletal muscle can be caused by genetic diseases such as malignant hyperthermia, central core disease, and Brody's disease. Malignant hyperthermia, an autosomal dominant trait, poses life-threatening risks during certain surgeries. Anesthetics like halothane or ether and the muscle relaxant succinylcholine can lead to uncontrolled release of calcium from the sarcoplasmic reticulum (SR), resulting in skeletal muscle rigidity, tachycardia, hyperventilation, and hyperthermia. Immediate treatment is essential to prevent fatality. There are currently tests involving muscle biopsy specimens to determine if a patient has malignant hyperthermia. The incidence of this condition is approximately 1 per 15,000 children and 1 per 50,000 adults who receive anesthesia. Malignant hyperthermia is caused by a defect in the sarcoplasmic reticulum calcium release channel (RYR) that becomes activated in the presence of the aforementioned anesthetics. This defect causes the release of calcium into the myoplasm, leading to prolonged muscle contraction (rigidity). The defect in RYR is not limited to a single locus. In some cases, malignant hyperthermia has been associated with a defect in the dihydropyridine receptor (DHPR) of the T-tubule.

Central core disease, an autosomal dominant trait, is a rare condition that results in muscle weakness, loss of mitochondria in the core of skeletal muscle fibers, and disintegration of contractile filaments. It is closely linked to malignant hyperthermia, so patients with central core disease are treated as if they are susceptible to malignant hyperthermia in surgical situations. It is hypothesized that central cores devoid of mitochondria represent areas with elevated intracellular calcium due to a mutation in the RYR. The loss of mitochondria is believed to occur when they take up the elevated calcium, leading to mitochondrial calcium overload.

Brody's disease is characterized by painless muscle cramping and impaired muscle relaxation during exercise. When an affected person engages in activities like running upstairs, their muscles may temporarily stiffen and become unusable. The relaxation of muscle involves a complex series of steps. First, the myosin head binds to actin, followed by a conformational change known as "ratchet action" that pulls the actin filament towards the center of the sarcomere. During this transition, myosin releases adenosine diphosphate (ADP) and inorganic phosphate. Binding of ATP to myosin reduces its affinity for actin, causing myosin to detach from the actin filament. Subsequently, myosin partially hydrolyzes ATP, using some of its energy to recock the head and return to the resting state.
GeneticdiseasesthatcausedisturbancesinCa++ homeostasisinskeletalmuscleincludemalignant hyperthermia, central core disease, andBrody’s disease. Malignanthyperthermiaisanautosomaldominanttraitthathaslife-threateningconsequencesincertainsurgicalinstances.AnestheticssuchashalothaneoretherandthemusclerelaxantsuccinylcholinecanproduceuncontrolledreleaseofCa++ fromtheSR,therebyresultinginskeletalmusclerigidity,tachycardia,hyperventilation,andhyperthermia.Thisconditionislethalifnottreatedimmediately.Therearecurrentlyaseriesoftests(involvingcontractileresponsesofmusclebiopsyspecimens)toassesswhetherapatienthasmalignanthyperthermia.Theincidenceofthisconditionisapproximately1per15,000childrenand1per50,000adultstreatedwithanesthetics.MalignanthyperthermiaistheresultofadefectintheSRCa++ releasechannel(RYR),whichbecomesactivatedinthepresenceoftheaforementionedanesthetics,causesthereleaseofCa++ intothemyoplasm,andhenceprolongsmusclecontraction(rigidity).ThedefectintheRYRisnotrestrictedtoasinglelocus.Insomecases,malignanthyperthermiahasbeenlinkedtoadefectintheDHPRoftheTtubule.
Centralcorediseaseisarareautosomaldominanttraitthatresultsinmuscleweakness,lossofmitochondriainthecoreofskeletalmusclefibers,andsomedisintegrationofcontractilefilaments.Itisoftencloselyassociatedwithmalignanthyperthermia,andsopatientswithcentralcorediseasearetreatedasthoughtheyaresusceptibletomalignanthyperthermiainsurgicalsituations.ItishypothesizedthatcentralcoresdevoidofmitochondriarepresentareasofelevatedintracellularCa++ secondarytoamutationintheRYR.ThelossofmitochondriaisthoughttooccurwhentheytakeuptheelevatedCa++ ,whichleadstomitochondrialCa++ overload.
Brody’sdiseaseischaracterizedbypainlessmusclecrampingandimpairedmusclerelaxationduringexercise.Whileanaffectedpersonrunsupstairs,forexample,musclesmaystiffenandtemporarilycannotbeused.Thisrelaxation myosin head to bind to the underlying actin (state b). Myosin next undergoes a conformational change termed “ratchet action” that pulls the actin filament toward the center of the sarcomere (state c). Myosin releases adenosine diphosphate (ADP) and inorganic phosphate during the transition to state c. Binding of ATP to myosin decreases the affinity of myosin for actin, thereby resulting in the release of myosin from the actin filament (state d). Myosin then partially hydrolyzes the ATP, and part of the energy in the ATP is used to recock the head and return to the resting state.