Activity of LKB1 and AMPK-related kinases in skeletal muscle: effects of contraction, phenformin, and AICAR

• Published in: American journal of physiology: endocrinology and metabolism Vol. 287; no. 2; pp. E310 - E317
• Main Authors: Sakamoto, Kei, Goransson, Olga, Hardie, D. Grahame, Alessi, Dario R
• Format: Journal Article
• Language: English
• Published: United States 01.08.2004
• Subjects: Aminoimidazole Carboxamide - analogs & derivatives; Aminoimidazole Carboxamide - pharmacology; AMP-Activated Protein Kinases; Animals; Cells, Cultured; Enzyme Activation - drug effects; Enzyme Activation - physiology; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; HeLa Cells; Humans; Hypoglycemic Agents - pharmacology; Isoenzymes - drug effects; Isoenzymes - metabolism; Male; Mice; Mice, Knockout; Multienzyme Complexes - drug effects; Multienzyme Complexes - metabolism; Muscle Contraction - physiology; Muscle, Skeletal - drug effects; Muscle, Skeletal - enzymology; Organ Culture Techniques; Phenformin - pharmacology; Physical Conditioning, Animal - physiology; Protein-Serine-Threonine Kinases - drug effects; Protein-Serine-Threonine Kinases - metabolism; Rats; Rats, Wistar; Ribonucleotides - pharmacology
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00074.2004

1 MRC Protein Phosphorylation Unit and 2 Division of Molecular Physiology, School of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom DD1 5EH Submitted 17 February 2004 ; accepted in final form 4 April 2004 Activation of AMP-activated protein kinase (AMPK) by exercise and metformin is beneficial for the treatment of type 2 diabetes. We recently found that, in cultured cells, the LKB1 tumor suppressor protein kinase activates AMPK in response to the metformin analog phenformin and the AMP mimetic drug 5-aminoimidazole-4-carboxamide-1- - D -ribofuranoside (AICAR). We have also reported that LKB1 activates 11 other AMPK-related kinases. The activity of LKB1 or the AMPK-related kinases has not previously been studied in a tissue with physiological relevance to diabetes. In this study, we have investigated whether contraction, phenformin, and AICAR influence LKB1 and AMPK-related kinase activity in rat skeletal muscle. Contraction in situ, induced via sciatic nerve stimulation, significantly increased AMPK 2 activity and phosphorylation in multiple muscle fiber types without affecting LKB1 activity. Treatment of isolated skeletal muscle with phenformin or AICAR stimulated the phosphorylation and activation of AMPK 1 and AMPK 2 without altering LKB1 activity. Contraction, phenformin, or AICAR did not significantly increase activities or expression of the AMPK-related kinases QSK, QIK, MARK2/3, and MARK4 in skeletal muscle. The results of this study suggest that muscle contraction, phenformin, or AICAR activates AMPK by a mechanism that does not involve direct activation of LKB1. They also suggest that the effects of excercise, phenformin, and AICAR on metabolic processes in muscle may be mediated through activation of AMPK rather than activation of LKB1 or the AMPK-related kinases. AMP-activated protein kinase; 5-aminoimidazole-4-carboxamide-1- - D -ribofuranoside Address for reprint requests and other correspondence: K. Sakamoto, MRC Protein Phosphorylation Unit, School of Life Sciences, Univ. of Dundee, Dow St., Dundee, Scotland, UK DD1 5EH (E-mail: k.sakamoto{at}dundee.ac.uk ).