miR-378a influences vascularization in skeletal muscles

Bart Krist; Paulina Podkalicka; Olga Mucha; Mateusz Mendel; Aleksandra Sępioł; Olga Martyna Rusiecka; Ewelina Józefczuk; Karolina Bukowska-Strakova; Anna Grochot-Przęczek; Mateusz Tomczyk; Damian Klóska; Mauro Giacca; Paweł Maga; Rafał Niżankowski; Alicja Józkowicz; Agnieszka Łoboda; Józef Dulak; Urszula Florczyk-Soluch

doi:10.1093/cvr/cvz236

miR-378a influences vascularization in skeletal muscles

Bart Krist, Paulina Podkalicka, Olga Mucha, Mateusz Mendel, Aleksandra Sępioł, Olga Martyna Rusiecka, Ewelina Józefczuk, Karolina Bukowska-Strakova, Anna Grochot-Przęczek, Mateusz Tomczyk, Damian Klóska, Mauro Giacca, Paweł Maga, Rafał Niżankowski, Alicja Józkowicz, Agnieszka Łoboda, Józef Dulak, Urszula Florczyk-Soluch

Cardiovascular Sciences

Research output: Contribution to journal › Article › peer-review

23 Citations (Scopus)

Abstract

AIMS: MicroRNA-378a, highly expressed in skeletal muscles, was demonstrated to affect myoblasts differentiation and to promote tumour angiogenesis. We hypothesized that miR-378a could play a pro-angiogenic role in skeletal muscle and may be involved in regeneration after ischaemic injury in mice. METHODS AND RESULTS: Silencing of miR-378a in murine C2C12 myoblasts did not affect differentiation but impaired their secretory angiogenic potential towards endothelial cells. miR-378a knockout (miR-378a-/-) in mice resulted in a decreased number of CD31-positive blood vessels and arterioles in gastrocnemius muscle. In addition, diminished endothelial sprouting from miR-378a-/- aortic rings was shown. Interestingly, although fibroblast growth factor 1 (Fgf1) expression was decreased in miR-378a-/- muscles, this growth factor did not mediate the angiogenic effects exerted by miR-378a. In vivo, miR-378a knockout did not affect the revascularization of the ischaemic muscles in both normo- and hyperglycaemic mice subjected to femoral artery ligation (FAL). No difference in regenerating muscle fibres was detected between miR-378a-/- and miR-378+/+ mice. miR-378a expression temporarily declined in ischaemic skeletal muscles of miR-378+/+ mice already on Day 3 after FAL. At the same time, in the plasma, the level of miR-378a-3p was enhanced. Similar elevation of miR-378a-3p was reported in the plasma of patients with intermittent claudication in comparison to healthy donors. Local adeno-associated viral vectors-based miR-378a overexpression was enough to improve the revascularization of the ischaemic limb of wild-type mice on Day 7 after FAL, what was not reported after systemic delivery of vectors. In addition, the number of infiltrating CD45+ cells and macrophages (CD45+ CD11b+ F4/80+ Ly6G-) was higher in the ischaemic muscles of miR-378a-/- mice, suggesting an anti-inflammatory action of miR-378a. CONCLUSIONS: Data indicate miR-378a role in the pro-angiogenic effect of myoblasts and vascularization of skeletal muscle. After the ischaemic insult, the anti-angiogenic effect of miR-378a deficiency might be compensated by enhanced inflammation.

Original language	English
Pages (from-to)	1386-1397
Number of pages	12
Journal	Cardiovascular Research
Volume	116
Issue number	7
DOIs	https://doi.org/10.1093/cvr/cvz236
Publication status	Published - 1 Jun 2020

Keywords

Angiogenesis
Hind limb ischaemia
MicroRNA-378a
Muscle regeneration
Myoblasts
Revascularization

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10.1093/cvr/cvz236

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Krist, B., Podkalicka, P., Mucha, O., Mendel, M., Sępioł, A., Rusiecka, O. M., Józefczuk, E., Bukowska-Strakova, K., Grochot-Przęczek, A., Tomczyk, M., Klóska, D., Giacca, M., Maga, P., Niżankowski, R., Józkowicz, A., Łoboda, A., Dulak, J., & Florczyk-Soluch, U. (2020). miR-378a influences vascularization in skeletal muscles. Cardiovascular Research, 116(7), 1386-1397. https://doi.org/10.1093/cvr/cvz236

@article{e95dba674cb44a22bbb02077355b523b,

title = "miR-378a influences vascularization in skeletal muscles",

abstract = "AIMS: MicroRNA-378a, highly expressed in skeletal muscles, was demonstrated to affect myoblasts differentiation and to promote tumour angiogenesis. We hypothesized that miR-378a could play a pro-angiogenic role in skeletal muscle and may be involved in regeneration after ischaemic injury in mice. METHODS AND RESULTS: Silencing of miR-378a in murine C2C12 myoblasts did not affect differentiation but impaired their secretory angiogenic potential towards endothelial cells. miR-378a knockout (miR-378a-/-) in mice resulted in a decreased number of CD31-positive blood vessels and arterioles in gastrocnemius muscle. In addition, diminished endothelial sprouting from miR-378a-/- aortic rings was shown. Interestingly, although fibroblast growth factor 1 (Fgf1) expression was decreased in miR-378a-/- muscles, this growth factor did not mediate the angiogenic effects exerted by miR-378a. In vivo, miR-378a knockout did not affect the revascularization of the ischaemic muscles in both normo- and hyperglycaemic mice subjected to femoral artery ligation (FAL). No difference in regenerating muscle fibres was detected between miR-378a-/- and miR-378+/+ mice. miR-378a expression temporarily declined in ischaemic skeletal muscles of miR-378+/+ mice already on Day 3 after FAL. At the same time, in the plasma, the level of miR-378a-3p was enhanced. Similar elevation of miR-378a-3p was reported in the plasma of patients with intermittent claudication in comparison to healthy donors. Local adeno-associated viral vectors-based miR-378a overexpression was enough to improve the revascularization of the ischaemic limb of wild-type mice on Day 7 after FAL, what was not reported after systemic delivery of vectors. In addition, the number of infiltrating CD45+ cells and macrophages (CD45+ CD11b+ F4/80+ Ly6G-) was higher in the ischaemic muscles of miR-378a-/- mice, suggesting an anti-inflammatory action of miR-378a. CONCLUSIONS: Data indicate miR-378a role in the pro-angiogenic effect of myoblasts and vascularization of skeletal muscle. After the ischaemic insult, the anti-angiogenic effect of miR-378a deficiency might be compensated by enhanced inflammation.",

keywords = "Angiogenesis, Hind limb ischaemia, MicroRNA-378a, Muscle regeneration, Myoblasts, Revascularization",

author = "Bart Krist and Paulina Podkalicka and Olga Mucha and Mateusz Mendel and Aleksandra S{\c e}pio{\l} and Rusiecka, {Olga Martyna} and Ewelina J{\'o}zefczuk and Karolina Bukowska-Strakova and Anna Grochot-Prz{\c e}czek and Mateusz Tomczyk and Damian Kl{\'o}ska and Mauro Giacca and Pawe{\l} Maga and Rafa{\l} Ni{\.z}ankowski and Alicja J{\'o}zkowicz and Agnieszka {\L}oboda and J{\'o}zef Dulak and Urszula Florczyk-Soluch",

year = "2020",

month = jun,

day = "1",

doi = "10.1093/cvr/cvz236",

language = "English",

volume = "116",

pages = "1386--1397",

journal = "Cardiovascular Research",

issn = "0008-6363",

publisher = "Oxford University Press",

number = "7",

}

Krist, B, Podkalicka, P, Mucha, O, Mendel, M, Sępioł, A, Rusiecka, OM, Józefczuk, E, Bukowska-Strakova, K, Grochot-Przęczek, A, Tomczyk, M, Klóska, D, Giacca, M, Maga, P, Niżankowski, R, Józkowicz, A, Łoboda, A, Dulak, J & Florczyk-Soluch, U 2020, 'miR-378a influences vascularization in skeletal muscles', Cardiovascular Research, vol. 116, no. 7, pp. 1386-1397. https://doi.org/10.1093/cvr/cvz236

TY - JOUR

T1 - miR-378a influences vascularization in skeletal muscles

AU - Krist, Bart

AU - Podkalicka, Paulina

AU - Mucha, Olga

AU - Mendel, Mateusz

AU - Sępioł, Aleksandra

AU - Rusiecka, Olga Martyna

AU - Józefczuk, Ewelina

AU - Bukowska-Strakova, Karolina

AU - Grochot-Przęczek, Anna

AU - Tomczyk, Mateusz

AU - Klóska, Damian

AU - Giacca, Mauro

AU - Maga, Paweł

AU - Niżankowski, Rafał

AU - Józkowicz, Alicja

AU - Łoboda, Agnieszka

AU - Dulak, Józef

AU - Florczyk-Soluch, Urszula

PY - 2020/6/1

Y1 - 2020/6/1

N2 - AIMS: MicroRNA-378a, highly expressed in skeletal muscles, was demonstrated to affect myoblasts differentiation and to promote tumour angiogenesis. We hypothesized that miR-378a could play a pro-angiogenic role in skeletal muscle and may be involved in regeneration after ischaemic injury in mice. METHODS AND RESULTS: Silencing of miR-378a in murine C2C12 myoblasts did not affect differentiation but impaired their secretory angiogenic potential towards endothelial cells. miR-378a knockout (miR-378a-/-) in mice resulted in a decreased number of CD31-positive blood vessels and arterioles in gastrocnemius muscle. In addition, diminished endothelial sprouting from miR-378a-/- aortic rings was shown. Interestingly, although fibroblast growth factor 1 (Fgf1) expression was decreased in miR-378a-/- muscles, this growth factor did not mediate the angiogenic effects exerted by miR-378a. In vivo, miR-378a knockout did not affect the revascularization of the ischaemic muscles in both normo- and hyperglycaemic mice subjected to femoral artery ligation (FAL). No difference in regenerating muscle fibres was detected between miR-378a-/- and miR-378+/+ mice. miR-378a expression temporarily declined in ischaemic skeletal muscles of miR-378+/+ mice already on Day 3 after FAL. At the same time, in the plasma, the level of miR-378a-3p was enhanced. Similar elevation of miR-378a-3p was reported in the plasma of patients with intermittent claudication in comparison to healthy donors. Local adeno-associated viral vectors-based miR-378a overexpression was enough to improve the revascularization of the ischaemic limb of wild-type mice on Day 7 after FAL, what was not reported after systemic delivery of vectors. In addition, the number of infiltrating CD45+ cells and macrophages (CD45+ CD11b+ F4/80+ Ly6G-) was higher in the ischaemic muscles of miR-378a-/- mice, suggesting an anti-inflammatory action of miR-378a. CONCLUSIONS: Data indicate miR-378a role in the pro-angiogenic effect of myoblasts and vascularization of skeletal muscle. After the ischaemic insult, the anti-angiogenic effect of miR-378a deficiency might be compensated by enhanced inflammation.

AB - AIMS: MicroRNA-378a, highly expressed in skeletal muscles, was demonstrated to affect myoblasts differentiation and to promote tumour angiogenesis. We hypothesized that miR-378a could play a pro-angiogenic role in skeletal muscle and may be involved in regeneration after ischaemic injury in mice. METHODS AND RESULTS: Silencing of miR-378a in murine C2C12 myoblasts did not affect differentiation but impaired their secretory angiogenic potential towards endothelial cells. miR-378a knockout (miR-378a-/-) in mice resulted in a decreased number of CD31-positive blood vessels and arterioles in gastrocnemius muscle. In addition, diminished endothelial sprouting from miR-378a-/- aortic rings was shown. Interestingly, although fibroblast growth factor 1 (Fgf1) expression was decreased in miR-378a-/- muscles, this growth factor did not mediate the angiogenic effects exerted by miR-378a. In vivo, miR-378a knockout did not affect the revascularization of the ischaemic muscles in both normo- and hyperglycaemic mice subjected to femoral artery ligation (FAL). No difference in regenerating muscle fibres was detected between miR-378a-/- and miR-378+/+ mice. miR-378a expression temporarily declined in ischaemic skeletal muscles of miR-378+/+ mice already on Day 3 after FAL. At the same time, in the plasma, the level of miR-378a-3p was enhanced. Similar elevation of miR-378a-3p was reported in the plasma of patients with intermittent claudication in comparison to healthy donors. Local adeno-associated viral vectors-based miR-378a overexpression was enough to improve the revascularization of the ischaemic limb of wild-type mice on Day 7 after FAL, what was not reported after systemic delivery of vectors. In addition, the number of infiltrating CD45+ cells and macrophages (CD45+ CD11b+ F4/80+ Ly6G-) was higher in the ischaemic muscles of miR-378a-/- mice, suggesting an anti-inflammatory action of miR-378a. CONCLUSIONS: Data indicate miR-378a role in the pro-angiogenic effect of myoblasts and vascularization of skeletal muscle. After the ischaemic insult, the anti-angiogenic effect of miR-378a deficiency might be compensated by enhanced inflammation.

KW - Angiogenesis

KW - Hind limb ischaemia

KW - MicroRNA-378a

KW - Muscle regeneration

KW - Myoblasts

KW - Revascularization

UR - http://www.scopus.com/inward/record.url?scp=85082705589&partnerID=8YFLogxK

U2 - 10.1093/cvr/cvz236

DO - 10.1093/cvr/cvz236

M3 - Article

C2 - 31504257

AN - SCOPUS:85082705589

SN - 0008-6363

VL - 116

SP - 1386

EP - 1397

JO - Cardiovascular Research

JF - Cardiovascular Research

IS - 7

ER -

miR-378a influences vascularization in skeletal muscles

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Keywords

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