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Cell Metab. 2015 Jun 2;21(6):883-90. doi: 10.1016/j.cmet.2015.05.016.

AMPK activation of muscle autophagy prevents fasting-induced hypoglycemia and myopathy during aging.

Author information

1
Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON L8N 3Z5, Canada.
2
Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON L8N 3Z5, Canada; Department of Pediatrics, McMaster University, 1280 Main Street West, Hamilton, ON L8N 3Z5, Canada.
3
St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, VIC 3065, Australia.
4
Department of Pathology and Molecular Medicine, McMaster University, 1280 Main Street West, Hamilton, ON L8N 3Z5, Canada.
5
Department of Pediatrics, McMaster University, 1280 Main Street West, Hamilton, ON L8N 3Z5, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON L8N 3Z5, Canada.
6
Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON L8N 3Z5, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON L8N 3Z5, Canada. Electronic address: gsteinberg@mcmaster.ca.

Abstract

The AMP-activated protein kinase (AMPK) activates autophagy, but its role in aging and fasting-induced muscle function has not been defined. Here we report that fasting mice lacking skeletal muscle AMPK (AMPK-MKO) results in hypoglycemia and hyperketosis. This is not due to defective fatty acid oxidation, but instead is related to a block in muscle proteolysis that leads to reduced circulating levels of alanine, an essential amino acid required for gluconeogenesis. Markers of muscle autophagy including phosphorylation of Ulk1 Ser555 and Ser757 and aggregation of RFP-LC3 puncta are impaired. Consistent with impaired autophagy, aged AMPK-MKO mice possess a significant myopathy characterized by reduced muscle function, mitochondrial disease, and accumulation of the autophagy/mitophagy proteins p62 and Parkin. These findings establish an essential requirement for skeletal muscle AMPK-mediated autophagy in preserving blood glucose levels during prolonged fasting as well as maintaining muscle integrity and mitochondrial function during aging.

PMID:
26039451
PMCID:
PMC5233441
DOI:
10.1016/j.cmet.2015.05.016
[Indexed for MEDLINE]
Free PMC Article

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