Kcnma1 is involved in mitochondrial homeostasis in diabetes-related skeletal muscle atrophy

被引:2
作者
Gao, Shan-Yan [1 ,2 ,3 ]
Liu, Yong-Ping [4 ]
Wen, Ri [4 ]
Huang, Xin-Mei [5 ]
Li, Ping [6 ]
Yang, Yu-Hang [4 ]
Yang, Ni [4 ,7 ]
Zhang, Tie-Ning [1 ,2 ,3 ,4 ,7 ]
机构
[1] China Med Univ, Shengjing Hosp, Key Lab Precis Med Res Major Chron Dis, Shenyang, Peoples R China
[2] China Med Univ, Shengjing Hosp, Clin Res Ctr, Shenyang, Peoples R China
[3] China Med Univ, Shengjing Hosp, Dept Clin Epidemiol, Shenyang, Peoples R China
[4] China Med Univ, Shengjing Hosp, Dept Pediat, Shenyang, Peoples R China
[5] Fudan Univ, Shanghai Peoples Hosp 5, Dept Endocrinol, Shanghai, Peoples R China
[6] China Med Univ, Shengjing Hosp, Dept Endocrinol, Shenyang, Peoples R China
[7] China Med Univ, Dept Pediat, Shengjing Hosp, 36,SanHao St, Shenyang 110004, Liaoning, Peoples R China
基金
中国国家自然科学基金;
关键词
diabetes; Kcnma1; mitochondrial homeostasis; skeletal muscle loss; FREE FATTY-ACIDS; DB/DB MOUSE MODEL; INSULIN-RESISTANCE; TYPE-2; SUPPRESSION; PALMITATE;
D O I
10.1096/fj.202201397RR
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Uncontrolled diabetes causes a catabolic state with multi-organic complications, of which impairment on skeletal muscle contributes to the damaged mobility. Kcnma1 gene encodes the pore-forming alpha-subunit of Ca2+- and voltage-gated K+ channels of large conductance (BK channels), and loss-of-function mutations in Kcnma1 are in regards to impaired myogenesis. Herein, we observed a time-course reduction of Kcnma1 expression in the tibialis anterior muscles of leptin receptor-deficient (db/db) diabetic mice. To investigate the role of Kcnma1 in diabetic muscle atrophy, muscle-specific knockdown of Kcnma1 was achieved by mice receiving intravenous injection of adeno-associated virus-9 (AAV9)-encoding shRNA against Kcnma1 under the muscle creatine kinase (MCK) promoter. Impairment on muscle mass and myogenesis were observed in m/m mice with AAV9-shKcnma1 intervention, while this impairment was more obvious in diabetic db/db mice. Simultaneously, damaged mitochondrial dynamics and biogenesis showed much severer in db/db mice with AAV9-shKcnma1 intervention. RNA sequencing revealed the large transcriptomic changes resulted by Kcnma1 knockdown, and changes in mitochondrial homeostasis-related genes were validated. Besides, the artificial alteration of Kcnma1 in mouse C2C12 myoblasts was achieved with an adenovirus vector. Consistent results were demonstrated by Kcnma1 knockdown in palmitate-treated cells, whereas opposite results were exhibited by Kcnma1 overexpression. Collectively, we document Kcnma1 as a potential keeper of mitochondrial homeostasis, and the loss of Kcnma1 is a critical event in priming skeletal muscle loss in diabetes.
引用
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页数:18
相关论文
共 49 条
  • [1] Mitochondrial Dysfunction in Skeletal Muscle Pathologies
    Abrigo, Johanna
    Simon, Felipe
    Cabrera, Daniel
    Vilos, Cristian
    Cabello-Verrugio, Claudio
    [J]. CURRENT PROTEIN & PEPTIDE SCIENCE, 2019, 20 (06) : 536 - 546
  • [2] Mitochondria Initiate and Regulate Sarcopenia
    Alway, Stephen E.
    Mohamed, Junaith S.
    Myers, Matthew J.
    [J]. EXERCISE AND SPORT SCIENCES REVIEWS, 2017, 45 (02): : 58 - 69
  • [3] Amer Diabet Assoc, 2014, DIABETES CARE, V37, pS81, DOI [10.2337/dc11-S062, 10.2337/dc14-S081, 10.2337/dc11-S011, 10.2337/dc12-s064, 10.2337/dc13-S067, 10.2337/dc13-S011, 10.2337/dc10-S062, 10.2337/dc12-s011, 10.2337/dc10-S011]
  • [4] Mitochondrial cAMP-PKA signaling: What do we really know?
    Amer, Yasmine Ould
    Hebert-Chatelain, Etienne
    [J]. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS, 2018, 1859 (09): : 868 - 877
  • [5] Mitochondrial BKCa channel
    Balderas, Enrique
    Zhang, Jin
    Stefani, Enrico
    Toro, Ligia
    [J]. FRONTIERS IN PHYSIOLOGY, 2015, 6
  • [6] Skeletal muscle dysfunction in the db/db mouse model of type 2 diabetes
    Bayley, Jeppe Seamus
    Pedersen, Thomas Holm
    Nielsen, Ole Baekgaard
    [J]. MUSCLE & NERVE, 2016, 54 (03) : 460 - 468
  • [7] Free fatty acids and pathogenesis of type 2 diabetes mellitus
    Bergman, RN
    Ader, M
    [J]. TRENDS IN ENDOCRINOLOGY AND METABOLISM, 2000, 11 (09) : 351 - 356
  • [8] Effects of free fatty acids (FFA) on glucose metabolism: Significance for insulin resistance and type 2 diabetes
    Boden, G
    [J]. EXPERIMENTAL AND CLINICAL ENDOCRINOLOGY & DIABETES, 2003, 111 (03) : 121 - 124
  • [9] Skeletal Muscle Insulin Resistance Is the Primary Defect in Type 2 Diabetes
    DeFronzo, Ralph A.
    Tripathy, Devjit
    [J]. DIABETES CARE, 2009, 32 : S157 - S163
  • [10] Carnosic Acid Attenuates the Free Fatty Acid-Induced Insulin Resistance in Muscle Cells and Adipocytes
    Den Hartogh, Danja J.
    Vlavcheski, Filip
    Giacca, Adria
    MacPherson, Rebecca E. K.
    Tsiani, Evangelia
    [J]. CELLS, 2022, 11 (01)