Ultrastructural changes in myocardial cells of mice with dysferlinopathy (Bla/J line)

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Abstract

BACKGROUND: Striated cardiac muscle tissue in dysferlinopathy, a rare hereditary muscular dystrophy, has been the subject of limited research. Dysferlinopathy is traditionally considered a disease that predominantly affects skeletal muscles, as clinically significant heart failure is rare in affected individuals. However, myocardial involvement due to hereditary dysferlin deficiency has been described in only a few studies. The development of heart failure in these patients may result from both circulatory remodeling due to hypodynamia and direct myocardial damage. Structural changes observed in Bla/J mice with dysferlinopathy provide evidence for direct myocardial damage. However, submicroscopic alterations in cardiomyocytes and stromal myocardial cells (fibroblasts, endothelial cells, telocytes), as well as their role in the pathomorphogenesis of dysferlinopathy, remain insufficiently studied.

AIM: To characterize the ultrastructure of cardiomyocytes and stromal myocardial cells in the left ventricle of dysferlin-deficient Bla/J mice.

METHODS: Myocardial left ventricle fragments from Bla/J and C57BL/6 (control group) mice at 3, 6, 9, and 12 months of age were fixed and embedded in Araldite resin. Ultrathin sections (50–100 nm) were prepared, stained using Reynolds’ method, and examined via transmission electron microscopy.

RESULTS: Ultrastructural changes in the myocardium of Bla/J dysferlin-deficient mice included: destruction of the sarcolemma and intercalated discs; expansion and vacuolization of the sarcoplasmic reticulum; mitochondrial polymorphism. Additionally, myelin-like structures were detected in subsarcolemmal spaces and sarcoplasmic reticulum cisterns. In dysferlin-deficient mice, telocytes exhibited signs of degeneration. In contrast, the control group (C57BL/6 mice) showed no significant ultrastructural changes.

CONCLUSION: Ultrastructural evidence of myocardial damage in dysferlin-deficient Bla/J mice suggests a potential role of dysferlin in maintaining the structural integrity of cardiomyocytes and stromal cells.

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About the authors

Igor S. Limaev

Petrovsky National Research Centre of Surgery

Author for correspondence.
Email: is.limaev@proton.me
ORCID iD: 0000-0002-0994-9787
SPIN-code: 4909-6550
Russian Federation, Moscow

Ivan A. Yakovlev

Genotarget LLC

Email: ivan@ivan-ya.ru
ORCID iD: 0000-0001-8127-4078
SPIN-code: 8222-2234

MD, Cand. Sci. (Medicine)

Russian Federation, Moscow

Irina A. Chekmareva

Petrovsky National Research Centre of Surgery; A.V. Vishnevsky National Medical Research Center of Surgery

Email: chia236@mail.ru
ORCID iD: 0000-0003-0126-4473
SPIN-code: 5994-7650

Dr. Sci. (Biology)

Russian Federation, Moscow; Moscow

Sergey N. Bardakov

Military Medical Academy named after S.M. Kirov

Email: epistaxis@mail.ru
ORCID iD: 0000-0002-3804-6245
SPIN-code: 2351-4096

MD, Cand. Sci. (Medicine)

Russian Federation, Saint Petersburg

Aleksey M. Emelin

Petrovsky National Research Centre of Surgery

Email: eamar40rn@gmail.com
ORCID iD: 0000-0003-4109-0105
SPIN-code: 5605-1140
Russian Federation, Moscow

Maria A. Savelyeva

North-Western State Medical University named after I.I. Mechnikov

Email: savelyeva.mariaanat@yandex.ru
ORCID iD: 0009-0008-5667-115X
SPIN-code: 9935-5416
Russian Federation, Saint Petersburg

Alexey V. Deykin

Belgorod National Research University

Email: alexei@deikin.ru
ORCID iD: 0000-0001-9960-0863
SPIN-code: 8371-5197

Cand. Sci. (Biology)

Russian Federation, Belgorod

Roman V. Deev

Petrovsky National Research Centre of Surgery; Genotarget LLC

Email: romdey@gmail.com
ORCID iD: 0000-0001-8389-3841
SPIN-code: 2957-1687

Cand. Sci. (Medicine)

Russian Federation, Moscow; Moscow

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2. Fig. 1. Ultrastructure of the left ventricular myocardium in 3-month-old Bla/J mice: a, destruction of myofibrils; ×17,000; b, swollen, enlarged mitochondrion (marked with an asterisk) among mitochondria with electron-dense matrix, ×14,000; c, myelin-like structures in the subsarcolemmal space (marked with an asterisk), ×17,000; d, destructively altered sarcolemma (indicated by black arrows), ×23,000; e, signs of endothelial cell (EN) destruction and myelin-like inclusions (indicated by white arrows), ×14,000; f, telocyte in the stroma adjacent to a cardiomyocyte, ×8,900.

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3. Fig. 2. Aggregates of telocytes in the myocardial stroma of 3-month-old C57BL/6 mice (electron micrograph montage, ×4,000).

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4. Fig. 3. Ultrastructure of the left ventricular myocardium in 6-month-old Bla/J mice: a, mitochondrial polymorphism, ×23,000; b, mild edema in the area of the intercalated disc, ×23,000; c, functionally active fibroblast, ×12,000; d, degenerative changes in telocytes (TC) adjacent to a cardiomyocyte (CM), short telopodes (indicated by arrows) with podoms (arrowheads), ×17,000.

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5. Fig. 4. Ultrastructure of the left ventricular myocardium in 9–12-month-old Bla/J mice: a, myelin-like inclusions (indicated by arrows) in dilated cisterns of the sarcoplasmic reticulum, ×12,000; b, mild edema in the area of the intercalated disc of a cardiomyocyte, ×17,000; c, degenerative telocyte (marked with an asterisk), ×8,900; d, telocyte (indicated by an arrow) in contact with a cardiomyocyte (CM) and an endothelial cell (EN), ×12,000.

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