Research Interests

1) Alteration to Ca2+ handling in muscle during aging

2) Aberrant Ca2+ entry in Duchenne muscular dystrophy

3) Cellular membrane remodeling and repair

4) Regulation of Ca2+ homeostasis by lipid signaling

Research Description

Our studies center on analysis the molecular machinery that mediates excitation-contraction coupling during physiological and pathophysiological states. Recent publications have established that altered Ca2+ spark signaling is observed in skeletal muscle fibers from aged and dystrophic muscle fibers. These Ca2+ sparks are regulated by lipid signaling cascades and may play a role in modulating Ca2+ entry into muscle cells. Perturbation of the capacity of muscle cells to control Ca2+ entry has been linked to the pathology observed in muscular dystrophy. Additionally, alteration of the cellular membrane repair and remodeling mechanisms is thought to contribute to the progression of muscular dystrophy. Study of these related mechanisms and the disruption of such processes in disease states and aging muscle should lead to potential therapeutic approaches for muscle disorders that involve aberrant Ca2+ handling.

Pathology core facility

The pathology core facility has the capacity to process samples for paraffin embedded histology or for cryosections. An automated tissue processor and embedding station allow for the generation of paraffin embedded blocks. Both microtomes and a cryostat are available for investigator use in preparing samples. Standard histological staining can be conducted under appropriate conditions in the pathology core. Additionally, the core contains a full tissue culture suite for the preparation and culture of primary tissue culture samples from animals. An epi-fluorescence microscope with digital camera is also available for use during histochemical staining experiments.

Publications:

Cai C*, Weisleder N* , Ko JK, Komazaki S, Sunada Y, Nishi M, Takeshima H, Ma J. Membrane repair defects in muscular dystrophy are linked to altered interaction between MG53, caveolin-3 and dysferlin. J Biol Chem. 2009 Jun 5;284(23):15894-902. (* Equal contributors )

Weisleder N , Takeshima H, Ma J. Mitsugumin 53 (MG53) facilitates vesicle trafficking in striated muscle to contribute to cell membrane repair. Communicative & Integrative Biology . 2009 March/April 2(3):1-2. Invited review

Cai C, Masumiya H, Weisleder N , Matsuda N, Nishi M, Hwang M, Ko JK, Lin P, Thornton A, Zhao X, Pan Z, Komazaki S, Brotto M, Takeshima H, Ma J. MG53 nucleates assembly of cell membrane repair machinery. Nat Cell Biol. 2009 Jan;11(1):56-64.

Cai C*, Masumiya H*, Weisleder N* , Pan Z, Nishi M, Komazaki S, Takeshima H, Ma J. MG53 regulates membrane budding and exocytosis in muscle cells . J Biol Chem. 2009 Jan 30;284(5):3314-22. (* Equal contributors )

Li N, Lin P, Cai C, Pan Z, Weisleder N , Ma J. The amino-terminal peptide of Bax perturbs intracellular Ca2+ homeostasis to enhance apoptosis in prostate cancer cells. Am J Physiol Cell Physiol. 2009 Feb;296(2):C267-72.

Mavroidis M, Panagopoulou P, Kostavasili I, Weisleder N , Capetanaki Y. A missense mutation in desmin tail domain linked to human dilated cardiomyopathy promotes cleavage of the head domain and abolishes its Z-disc localization. FASEB J. 2008 Sep;22(9):3318-27.

Zhao X*, Weisleder N* , Thornton A, Oppong Y, Campbell R, Ma J, Brotto M. Compromised store-operated Ca(2+) entry in aged skeletal muscle. Aging Cell . 2008 Aug;7(4):561-8. (* Equal contributors )

Weisleder N , Ma J. Altered Ca(2+) sparks in aging skeletal and cardiac muscle. Ageing Res Rev. 2008 Jul;7(3):177-88. Invited review

Zhu H, Weisleder N , Wu P, Cai C, Chen JW. Caveolae/Caveolin-1 are important modulators of store-operated calcium entry in hs578/t breast cancer cells. J Pharmacol Sci. 2008 Feb;106(2):287-94.

Weisleder, N. , Takeshima, H., Ma, J. Immuno-proteomic approach to excitation-contraction coupling in skeletal and cardiac muscle: Molecular insights revealed by the mitsugumins. Cell Calcium . 2008 Jan;43(1):1-8. Invited review

Weisleder, N. , Ferrante, C., Hirata, Y., Collet, C., Chu , Y., Cheng, H., Takeshima, H., and Ma, J. Systemic ablation of RyR3 alters Ca 2+ spark signaling in adult skeletal muscle. Cell Calcium 2007 Dec;42(6):548-55.

Ko, J.K., Choi, K.H., Pan, Z., Lin, P., Weisleder, N. , Kim, C.W., Ma, J. The tail-anchoring domain of Bfl1 and HCCS1 targets mitochondrial membrane permeability to induce apoptosis . J Cell Sci. 2007 Aug 15;120(Pt 16):2912-23.

Yazawa, M., Ferrante, C., Feng, Y., Mio, K., Ogura, T., Zhang, M., Lin, P., Pan, Z., Komazaki, S., Kato, K., Nishi, M., Zhao, X., Weisleder, N. , Sato, C., Ma, J. and Takeshima, H. TRIC channels essential for Ca 2+ handling in intracellular stores. Nature 2007 Jul 5;448(7149):78-82.

Landstrom, A.P.*, Weisleder. N.* , Batalden, K.B., Martijn Bos, J., Tester, D.J., Ommen, S.R., Wehrens, X.H., Claycomb, W.C., Ko, J.K., Hwang, M., Pan, Z., Ma, J., Ackerman, M.J. Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans. J Mol Cell Cardiol. 2007 Jun;42(6):1026-35. (* Equal contributors )

Brotto, M., Weisleder, N. , Ma, J. Store-Operated Ca 2+ Entry in Muscle Physiology. Current Chemical Biology. 2007 Jan 1; 1(1):87-95. Invited Review

Weisleder, N.* , Brotto, M. * , Komazaki, S., Pan, Z., Zhao, X., Nosek, T., Parness, T., Takeshima, H., Ma, J. Muscle aging is associated with compromised Ca 2+ spark signaling and segregated intracellular Ca 2+ release. J Cell Biol . 2006 Aug 28;174(5): 639-45. (* Equal contributors )

Weisleder, N. , Ma, J. Ca 2+ sparks as a plastic signal for muscle health, aging and dystrophy. Acta Pharmacologica Sinca . 2006 Jul 27;27(7): 791-798. Invited Review

Zhao, X., Weisleder, N ., Han, X., Pan, Z., Parness, J., Brotto, M., Ma, J. A zumolene inhibits a component of store-operated calcium entry coupled to the skeletal muscle ryanodine receptor. J. Biol. Chem. 2006 Nov 3;281(44):33477-86.

Hirata, Y., Brotto, M., Weisleder, N ., Chu, Y., Lin, P., Zhao, X., Thornton, Komazaki, S., Takeshima, S., Ma, J., Pan, Z. Uncoupling store-operated Ca2+ entry and altered Ca2+ release from sarcoplasmic reticulum through silencing of junctophilin genes. Biophysical J. 2006 Jun 15;90(12):4418-27.

Zhao, X., Yoshida, M., Brotto, L., Takeshima, H., Weisleder, N. , Hirata, Y., Nosek, T.M., Brotto, M., Ma, J. Enhanced resistance to fatigue and altered calcium handling properties of sarcalumenin knockout mice. Physiol Genomics . 2005 Sep 21;23(1):72-8.

Wang, X.*, Weisleder, N * . , Collet, C., Zhou, J., Chu , Y., Hirata, Y., Zhao, X., Pan, Z., Brotto, M., Cheng, H., Ma, J. Uncontrolled calcium sparks act as a dystrophic signal for

mammalian skeletal muscle. Nat Cell Biol . 2005 May;7(5):525-30. (* Equal contributors )

Fountoulakis, M., Soumaka, E., Rapti, K., Mavroidis, M., Tsangaris, G., Maris. A., Weisleder, N. , Capetanaki, Y. Alterations in the heart mitochondrial proteome in a desmin null heart failure model. J Mol Cell Cardiol. 2005 Mar;38(3):461-74.

Shah, S.B., Davis, J., Weisleder, N. , Kostavassili, I., McCulloch, A.D., Ralston, E., Capetanaki, Y., Lieber R.L. Structural and Functional Roles of Desmin in Mouse Skeletal Muscle during Passive Deformation. Biophys J . 2004 May;86(5):2993-3008.

Weisleder, N. , Taffet, G., Capetanaki, Y. Bcl-2 overexpression ameliorates inherited desmin null cardiomyopathy. Proc Natl Acad Sci U S A . 2004 Jan 20;101(3):769-74.

Weisleder, N. , Abassi, S., Soumaka, E., Taegtmeyer, H., Capetanaki, Y., Cardiomyocyte-specific desmin rescue of desmin null cardiomyopathy excludes vascular involvement. J Mol Cell Cardiol . 2004 Jan;36(1):121-8.

Milner, D., Mavroidis, M., Weisleder, N. , Capetanaki Y. Desmin cytoskeleton linked to muscle mitochondrial distribution and respiratory function . J Cell Biol . 2000 Sep 18;150 (6):1283-98