Dataset Information

Proteome-wide Changes in the mdx-4cv Spleen due to Pathophysiological Cross Talk with Dystrophin-Deficient Skeletal Muscle.

ABSTRACT: Duchenne muscular dystrophy is primarily characterized by progressive muscle wasting due to deficiency in the membrane cytoskeletal protein dystrophin but is also associated with body-wide cellular disturbances in a variety of non-muscle tissues. In this study, we have focused on the comparative proteomic analysis of the spleen and established considerable changes in this crucial secondary lymphoid organ from the genetic mdx-4cv mouse model of dystrophinopathy. An apparent short isoform of dystrophin and associated glycoproteins were identified in spleen by mass spectrometry but appear not be affected in muscular dystrophy. In contrast, the mdx-4cv spleen showed significant proteome-wide changes in other protein species that are involved in metabolism, signaling, and cellular architecture. Since the spleen plays a key role in the immune response, these proteomic alterations may reflect pathophysiological cross talk between the lymphoid system and dystrophic muscles, which are affected by both fiber degeneration and inflammation.

SUBMITTER: Dowling P

PROVIDER: S-EPMC7490529 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Proteome-wide Changes in the <i>mdx-4cv</i> Spleen due to Pathophysiological Cross Talk with Dystrophin-Deficient Skeletal Muscle.

Dowling Paul P Gargan Stephen S Zweyer Margit M Henry Michael M Meleady Paula P Swandulla Dieter D Ohlendieck Kay K

iScience 20200826 9

Duchenne muscular dystrophy is primarily characterized by progressive muscle wasting due to deficiency in the membrane cytoskeletal protein dystrophin but is also associated with body-wide cellular disturbances in a variety of non-muscle tissues. In this study, we have focused on the comparative proteomic analysis of the spleen and established considerable changes in this crucial secondary lymphoid organ from the genetic <i>mdx-4cv</i> mouse model of dystrophinopathy. An apparent short isoform o ...[more]

PMID: 32916630

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Project description:BackgroundIn Duchenne muscular dystrophy (DMD), loss of the membrane stabilizing protein dystrophin results in myofiber damage. Microinjury to dystrophic myofibers also causes secondary imbalances in sarcolemmic ion permeability and resting membrane potential, which modifies excitation-contraction coupling and increases proinflammatory/apoptotic signaling cascades. Although glucocorticoids remain the standard of care for the treatment of DMD, there is a need to investigate the efficacy of other pharmacological agents targeting the involvement of imbalances in ion flux on dystrophic pathology.Methodology/principal findingsWe designed a preclinical trial to investigate the effects of lansoprazole (LANZO) administration, a proton pump inhibitor, on the dystrophic muscle phenotype in dystrophin deficient (mdx) mice. Eight to ten week-old female mice were assigned to one of four treatment groups (n?=?12 per group): (1) vehicle control; (2) 5 mg/kg/day LANZO; (3) 5 mg/kg/day prednisolone; and (4) combined treatment of 5 mg/kg/day prednisolone (PRED) and 5 mg/kg/day LANZO. Treatment was administered orally 5 d/wk for 3 months. At the end of the study, behavioral (Digiscan) and functional outcomes (grip strength and Rotarod) were assessed prior to sacrifice. After sacrifice, body, tissue and organ masses, muscle histology, in vitro muscle force, and creatine kinase levels were measured. Mice in the combined treatment groups displayed significant reductions in the number of degenerating muscle fibers and number of inflammatory foci per muscle field relative to vehicle control. Additionally, mice in the combined treatment group displayed less of a decline in normalized forelimb and hindlimb grip strength and declines in in vitro EDL force after repeated eccentric contractions.Conclusions/significanceTogether our findings suggest that combined treatment of LANZO and prednisolone attenuates some components of dystrophic pathology in mdx mice. Our findings warrant future investigation of the clinical efficacy of LANZO and prednisolone combined treatment regimens in dystrophic pathology.

Dataset Information

Proteome-wide Changes in the mdx-4cv Spleen due to Pathophysiological Cross Talk with Dystrophin-Deficient Skeletal Muscle.

Publications

Proteome-wide Changes in the <i>mdx-4cv</i> Spleen due to Pathophysiological Cross Talk with Dystrophin-Deficient Skeletal Muscle.

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