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Volume 22
Issue 11
10.3390/ijms22115491
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Article

Reduction of Superoxide Dismutase 1 Delays Regeneration of Cardiotoxin-Injured Skeletal Muscle in KK/Ta-Ins2Akita Mice with Progressive Diabetic Nephropathy

by
Yuya Takahashi
1,
Tatsunori Shimizu
1,
Shunsuke Kato
1,
Mitsuhiko Nara
1,
Yumi Suganuma
1,
Takehiro Sato
1,
Tsukasa Morii
1,
Yuichiro Yamada
1,2 and
Hiroki Fujita
1,*
1
Department of Metabolism and Endocrinology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan
2
Kansai Electric Power Medical Research Institute, 2-1-7 Fukushima-ku, Osaka 553-0003, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(11), 5491; https://doi.org/10.3390/ijms22115491
Submission received: 12 April 2021 / Revised: 19 May 2021 / Accepted: 21 May 2021 / Published: 23 May 2021
(This article belongs to the Special Issue Oxidative Stress and Skeletal Muscle Function)
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Abstract

Superoxide dismutase (SOD) is a major antioxidant enzyme for superoxide removal, and cytoplasmic SOD (SOD1) is expressed as a predominant isoform in all cells. We previously reported that renal SOD1 deficiency accelerates the progression of diabetic nephropathy (DN) via increasing renal oxidative stress. To evaluate whether the degree of SOD1 expression determines regeneration capacity and sarcopenic phenotypes of skeletal muscles under incipient and advanced DN conditions, we investigated the alterations of SOD1 expression, oxidative stress marker, inflammation, fibrosis, and regeneration capacity in cardiotoxin (CTX)-injured tibialis anterior (TA) muscles of two Akita diabetic mouse models with different susceptibility to DN, DN-resistant C57BL/6-Ins2Akita and DN-prone KK/Ta-Ins2Akita mice. Here, we report that KK/Ta-Ins2Akita mice, but not C57BL/6-Ins2Akita mice, exhibit delayed muscle regeneration after CTX injection, as demonstrated by the finding indicating significantly smaller average cross-sectional areas of regenerating TA muscle myofibers relative to KK/Ta-wild-type mice. Furthermore, we observed markedly reduced SOD1 expression in CTX-injected TA muscles of KK/Ta-Ins2Akita mice, but not C57BL/6-Ins2Akita mice, along with increased inflammatory cell infiltration, prominent fibrosis and superoxide overproduction. Our study provides the first evidence that SOD1 reduction and the following superoxide overproduction delay skeletal muscle regeneration through induction of overt inflammation and fibrosis in a mouse model of progressive DN.
Keywords: akita mouse; cardiotoxin injury; diabetic nephropathy; muscle regeneration; oxidative stress; superoxide dismutase 1 akita mouse; cardiotoxin injury; diabetic nephropathy; muscle regeneration; oxidative stress; superoxide dismutase 1

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MDPI and ACS Style

Takahashi, Y.; Shimizu, T.; Kato, S.; Nara, M.; Suganuma, Y.; Sato, T.; Morii, T.; Yamada, Y.; Fujita, H. Reduction of Superoxide Dismutase 1 Delays Regeneration of Cardiotoxin-Injured Skeletal Muscle in KK/Ta-Ins2Akita Mice with Progressive Diabetic Nephropathy. Int. J. Mol. Sci. 2021, 22, 5491. https://doi.org/10.3390/ijms22115491

AMA Style

Takahashi Y, Shimizu T, Kato S, Nara M, Suganuma Y, Sato T, Morii T, Yamada Y, Fujita H. Reduction of Superoxide Dismutase 1 Delays Regeneration of Cardiotoxin-Injured Skeletal Muscle in KK/Ta-Ins2Akita Mice with Progressive Diabetic Nephropathy. International Journal of Molecular Sciences. 2021; 22(11):5491. https://doi.org/10.3390/ijms22115491

Chicago/Turabian Style

Takahashi, Yuya, Tatsunori Shimizu, Shunsuke Kato, Mitsuhiko Nara, Yumi Suganuma, Takehiro Sato, Tsukasa Morii, Yuichiro Yamada, and Hiroki Fujita. 2021. "Reduction of Superoxide Dismutase 1 Delays Regeneration of Cardiotoxin-Injured Skeletal Muscle in KK/Ta-Ins2Akita Mice with Progressive Diabetic Nephropathy" International Journal of Molecular Sciences 22, no. 11: 5491. https://doi.org/10.3390/ijms22115491

APA Style

Takahashi, Y., Shimizu, T., Kato, S., Nara, M., Suganuma, Y., Sato, T., Morii, T., Yamada, Y., & Fujita, H. (2021). Reduction of Superoxide Dismutase 1 Delays Regeneration of Cardiotoxin-Injured Skeletal Muscle in KK/Ta-Ins2Akita Mice with Progressive Diabetic Nephropathy. International Journal of Molecular Sciences, 22(11), 5491. https://doi.org/10.3390/ijms22115491

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