Altered expression, intracellular distribution and activity of lymphocyte calpain II in Duchenne muscular dystrophy

Sundaram, Jagannathan; Rao, V. Mohana; Meena, A K; Anandaraj, M.P.J.S.

doi:10.1016/j.cca.2006.05.004

Cited by 6 publications

(2 citation statements)

References 42 publications

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“…Several lines of evidence suggest that sustained elevation of cytosolic Ca 2+ levels underlies muscle pathology and dysfunction in DMD. First, increased cytosolic Ca 2+ levels enhance the expression and activity of calpains, the Ca 2+ dependent proteases in dystrophic muscles (Spencer et al, 1995;Hussain et al, 2000;Shanmuga Sundaram et al, 2006;Voit et al, 2017). Calpain activation results in proteolytic damage to cellular proteins and the myofibrillar network (Dayton et al, 1976;MacLennan et al, 1991;Bartoli and Richard, 2005).…”

Section: Introductionmentioning

confidence: 99%

Abnormal Calcium Handling in Duchenne Muscular Dystrophy: Mechanisms and Potential Therapies

et al. 2021

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Duchenne muscular dystrophy (DMD) is an X-linked muscle-wasting disease caused by the loss of dystrophin. DMD is associated with muscle degeneration, necrosis, inflammation, fatty replacement, and fibrosis, resulting in muscle weakness, respiratory and cardiac failure, and premature death. There is no curative treatment. Investigations on disease-causing mechanisms offer an opportunity to identify new therapeutic targets to treat DMD. An abnormal elevation of the intracellular calcium (Cai2+) concentration in the dystrophin-deficient muscle is a major secondary event, which contributes to disease progression in DMD. Emerging studies have suggested that targeting Ca2+-handling proteins and/or mechanisms could be a promising therapeutic strategy for DMD. Here, we provide an updated overview of the mechanistic roles the sarcolemma, sarcoplasmic/endoplasmic reticulum, and mitochondria play in the abnormal and sustained elevation of Cai2+ levels and their involvement in DMD pathogenesis. We also discuss current approaches aimed at restoring Ca2+ homeostasis as potential therapies for DMD.

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Section: Introductionmentioning

confidence: 99%

Abnormal Calcium Handling in Duchenne Muscular Dystrophy: Mechanisms and Potential Therapies

et al. 2021

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“…Calpains are involved in a variety of calcium-regulated biological processes, such as cell proliferation and differentiation, apoptosis, membrane fusion, signal transduction, and platelet activation. Enhanced calpain activity has been observed in a number of diseases including ischemic , and traumatic , brain injury, cancer, − muscular dystrophy, , cataracts, strokes, and neurological disorders like Alzheimer’s, , Huntington’s, and Parkinson’s , diseases and multiple sclerosis. , Involvement of calpains in a wide variety of biological processes and diseases makes them important targets for the development of inhibitors. There are several reviews on the roles of calpains in diseases. − …”

Section: Introductionmentioning

confidence: 99%

Peptidyl α-Ketoamides with Nucleobases, Methylpiperazine, and Dimethylaminoalkyl Substituents as Calpain Inhibitors

Ovat

Hampton

et al. 2010

J. Med. Chem.

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A series of peptidyl α-ketoamides with the general structure Cbz-L-Leu-D,L-AA-CONH-R were synthesized and evaluated as inhibitors for the cysteine proteases calpain I, calpain II and cathepsin B. Nucleobases, methylpiperazine and dimethylaminoalkyl groups were incorporated into the primed region of the inhibitors to generate compounds that potentially cross the bloodbrain barrier. Two of these compounds (Cbz-Leu-D,L-Abu-CONH-(CH 2 ) 3 -adenin-9-yl and CbzLeu-D,L-Abu-CONH-(CH 2 ) 3 -(4-methylpiperazin-1-yl) have been shown to have useful concentrations in the brain in animals. The best inhibitor for calpain I was Cbz-Leu-D,L-Abu-CONH-(CH 2 ) 3 -2-methoxyadenin-9-yl (K i = 23 nM) and the best inhibitor for calpain II was CbzLeu-D,L-Phe-CONH-(CH 2 ) 3 -adenin-9-yl (K i = 68 nM). Based on the crystal structure obtained with heterocyclic peptidyl α-ketoamides, we have improved inhibitor potency by introducing a small hydrophobic group on the adenine ring. These inhibitors have good potential to be used in the treatment of neurodegenerative diseases.

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Gene expression in blood of subjects with Duchenne muscular dystrophy

et al. 2008

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The objective of this study was to examine RNA expression in blood of subjects with Duchenne muscular dystrophy (DMD). Whole blood was collected into PAX gene tubes and RNA was isolated for 3- to 20-year-old males with DMD (n = 34) and for age- and gender-matched normal healthy controls (n = 21). DMD was confirmed by genetic testing in all subjects. RNA expression was measured on Affymetrix whole-genome human U133 Plus 2.0 GeneChips. Using a Benjamini-Hochberg false discovery rate of 0.05 to correct for multiple comparisons, an unpaired t test for DMD versus controls yielded 10,763 regulated probes with no fold change cutoff, 1,467 probes with >|1.5|-fold change, 191 probes with >|2.0|-fold change, and 59 probes with a >|2.5|-fold change. These genes (probes) separated DMD from controls using cluster analyses. Almost all of the genes regulated in peripheral blood were different from the genes reported to be regulated in diseased muscle of subjects with DMD. It is proposed that the genes regulated in blood of subjects with Duchenne muscular dystrophy are indicative, at least in part, of the immune response to the diseased DMD muscle. The regulated genes might be used to monitor therapy or provide novel targets for immune-directed therapy for DMD.

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Altered expression, intracellular distribution and activity of lymphocyte calpain II in Duchenne muscular dystrophy

Cited by 6 publications

References 42 publications

Abnormal Calcium Handling in Duchenne Muscular Dystrophy: Mechanisms and Potential Therapies

Abnormal Calcium Handling in Duchenne Muscular Dystrophy: Mechanisms and Potential Therapies

Peptidyl α-Ketoamides with Nucleobases, Methylpiperazine, and Dimethylaminoalkyl Substituents as Calpain Inhibitors

Gene expression in blood of subjects with Duchenne muscular dystrophy

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