Core D will perform the qualitative and quantitative histological and ultrastructural checks that are necessary to support all other Projects. The Core will not only supply various techniques of electron, phase contrast and confocal microscopy, but it will also operate at a high standard of quality and offer an expert critical evaluation of the results of experimental and molecular alterations. The uniform and consistent use of high quality images will allow the detection of even subtle alterations in protein-protein interactions and in the response of individual cell organelles that either are at the basis of altered functions or are the long term results of such alterations. It is clear that the overall ultrastructural response of the muscle fiber to mutations affecting excitation-contraction coupling are quite specific and offer considerable insight into causative effects. In the past period we have evidenced a strong fiber type- and gender-dependence of the pathology, that correspindes quite well with similar variations in function. Two general approaches are proposed. One is to define any alterations in the relationships between the major protein components of calcium release units (CRUs, triads in skeletal muscle) within the context of the mutation and the other is to follow the development of pathology (most specifically mitochondrial, myofibrillar and CRUs'alterations) through development and aging and in relation to the known functional effects of the mutation on CRUs'channels.This will be achieved by combining light microscope techniques (phase contrast of fibers whole mounts and confocal imaging of fluorescently immunolabeled fibers) with thin sectioning and freeze-fracture for electron microscopy supplemented by quantitative morphometry techniques. The core aims at defining the primary impact of each mutation on the macromelcular assembly of calcium release units within a short term and the secondary impact on SR, mitochondria and contractile material on the long term

Public Health Relevance

To understand the muscle pathology of MH susceptible individuals it will be crucial to detect if any subtle alterations in the relationship between key component of the calcium release units machinery (mostly DHPR and RyR) underlie the RyR function imbalance. To that effect, ultrastructure will be tested by different technical approaches at an early and a late age.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAR1-MLB)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Davis
United States
Zip Code
Yang, Zhong; Liu, Qiang; Mannix, Robert J et al. (2014) Mononuclear cells from dedifferentiation of mouse myotubes display remarkable regenerative capability. Stem Cells 32:2492-501
Burr, Adam R; Millay, Douglas P; Goonasekera, Sanjeewa A et al. (2014) Na+ dysregulation coupled with Ca2+ entry through NCX1 promotes muscular dystrophy in mice. Mol Cell Biol 34:1991-2002
Bannister, Roger A; Beam, Kurt G (2013) Impaired gating of an L-Type Ca(2+) channel carrying a mutation linked to malignant hyperthermia. Biophys J 104:1917-22
Brandom, Barbara W; Bina, Saiid; Wong, Cynthia A et al. (2013) Ryanodine receptor type 1 gene variants in the malignant hyperthermia-susceptible population of the United States. Anesth Analg 116:1078-86
Altamirano, Francisco; Lopez, Jose R; Henriquez, Carlos et al. (2012) Increased resting intracellular calcium modulates NF-ýýB-dependent inducible nitric-oxide synthase gene expression in dystrophic mdx skeletal myotubes. J Biol Chem 287:20876-87
Boncompagni, Simona; Protasi, Feliciano; Franzini-Armstrong, Clara (2012) Sequential stages in the age-dependent gradual formation and accumulation of tubular aggregates in fast twitch muscle fibers: SERCA and calsequestrin involvement. Age (Dordr) 34:27-41
Barrientos, Genaro C; Feng, Wei; Truong, Kim et al. (2012) Gene dose influences cellular and calcium channel dysregulation in heterozygous and homozygous T4826I-RYR1 malignant hyperthermia-susceptible muscle. J Biol Chem 287:2863-76
Yuen, Benjamin; Boncompagni, Simona; Feng, Wei et al. (2012) Mice expressing T4826I-RYR1 are viable but exhibit sex- and genotype-dependent susceptibility to malignant hyperthermia and muscle damage. FASEB J 26:1311-22
Giulivi, Cecilia; Ross-Inta, Catherine; Omanska-Klusek, Alicja et al. (2011) Basal bioenergetic abnormalities in skeletal muscle from ryanodine receptor malignant hyperthermia-susceptible R163C knock-in mice. J Biol Chem 286:99-113
Feng, Wei; Barrientos, Genaro C; Cherednichenko, Gennady et al. (2011) Functional and biochemical properties of ryanodine receptor type 1 channels from heterozygous R163C malignant hyperthermia-susceptible mice. Mol Pharmacol 79:420-31

Showing the most recent 10 out of 32 publications