Chronic kidney disease induces autophagy leading to dysfunction of mitochondria in skeletal muscle
| Autor: | Faten Hassounah, Liping Zhang, Janet D. Klein, Xiaonan H. Wang, Harold A. Franch, Matthew B. Hudson, Jie Du, Zhen Su |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Physiology Muscle Fibers Skeletal MFN2 Biology urologic and male genital diseases Cell Line GTP Phosphohydrolases Mitochondrial Proteins Mice 03 medical and health sciences Adenosine Triphosphate Internal medicine Myosin Autophagy medicine Animals RNA Messenger Renal Insufficiency Chronic Muscle Skeletal Uremia Organelle Biogenesis Myogenesis High Mobility Group Proteins Membrane Proteins Skeletal muscle TFAM Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Mitochondria Muscle DNA-Binding Proteins Mice Inbred C57BL Disease Models Animal Muscular Atrophy 030104 developmental biology medicine.anatomical_structure Endocrinology Gene Expression Regulation Biochemistry Mitochondrial biogenesis mitochondrial fusion Beclin-1 Microtubule-Associated Proteins Research Article |
| Zdroj: | American Journal of Physiology-Renal Physiology. 312:F1128-F1140 |
| ISSN: | 1522-1466 1931-857X |
| Popis: | Chronic kidney disease (CKD) causes loss of lean body mass by multiple mechanisms. This study examines whether autophagy-mediated proteolysis contributes to CKD-induced muscle wasting. We tested autophagy in the muscle of CKD mice with plantaris muscle overloading to mimic resistance exercise or with acupuncture plus low-frequency electrical stimulation (Acu/LFES) treatment. In CKD muscle, Bnip3, Beclin-1, and LC3II mRNAs and proteins were increased compared with those in control muscle, indicating autophagosome-lysosome formation induction. Acu/LFES suppressed the CKD-induced upregulation of autophagy. However, overloading increased autophagy-related proteins in normal and CKD muscle. Serum from uremic mice induces autophagy formation but did not increase the myosin degradation or actin break down in cultured muscle satellite cells. We examined mitochondrial biogenesis, copy number, and ATP production in cultured myotubes, and found all three aspects to be decreased by uremic serum. Inhibition of autophagy partially reversed this decline in cultured myotubes. In CKD mice, the mitochondrial copy number, biogenesis marker peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), mitochondrial transcription factor A (TFAM), and mitochondrial fusion marker Mitofusin-2 (Mfn2) are decreased. Both muscle overloading and Acu/LFES increased mitochondrial copy number, and reversed the CKD-induced decreases in PGC-1α, TFAM, and Mfn2. We conclude that the autophagy is activated in the muscle of CKD mice. However, myofibrillar protein is not directly broken down through autophagy. Instead, CKD-induced upregulation of autophagy leads to dysfunction of mitochondria and decrease of ATP production. |
| Databáze: | OpenAIRE |
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