Effects of calcineurin activation on insulin-, AICAR- and contraction-induced glucose transport in skeletal muscle.
Skeletal muscle is composed of fast- and slow-twitch fibres with distinctive physiological and metabolic properties. The calmodulin-activated serine/threonine protein phosphatase calcineurin activates fast- to slow-twitch skeletal muscle remodelling through the induction of the slow-twitch skeletal muscle fibre gene expression programme, thereby enhancing insulin-stimulated glucose uptake and offering protection against dietary-induced insulin resistance. Given the profound influence of skeletal muscle fibre type on insulin-mediated responses, we determined whether the fast- to slow-twitch fibre-type transformation leads to alterations in insulin-independent glucose uptake in transgenic mice expressing a constitutively active form of calcineurin (MCK-CnA* mice). We determined whether skeletal muscle remodelling by activated calcineurin alters glucose transport in response to the AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide-beta-D-ribofuranoside (AICAR) or muscle contraction, two divergent insulin-independent activators of glucose transport. While insulin-stimulated glucose transport was increased 52%, the AICAR effect on glucose transport was 27% lower in MCK-CnA* mice versus wild-type mice (P < 0.05). In contrast, glucose transport was similar between genotypes after in vitro muscle contraction. Fibre-type transformation was associated with increased AMPKgamma1, decreased AMPKgamma3 and unchanged AMPKgamma2 protein expression between MCK-CnA* and wild-type mice (P < 0.05). The loss of AICAR-mediated glucose uptake is coupled to changes in the AMPK isoform expression, suggesting fibre-type dependence of the AICAR responses on glucose uptake. In conclusion, improvements in skeletal muscle glucose transport in response to calcineurin-induced muscle remodelling are limited to insulin action.
Department of Physiology, Section of Integrative Physiology, Karolinska Institute, von Eulers väg 4, II, SE-171 77 Stockholm, Sweden.
Jeffrey W
JW
Ryder
Yun Chau
YC
Long
Elisabeth
E
Nilsson
Margit
M
Mahlapuu
Juleen R
JR
Zierath
D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active; D019703:Calcineurin / Q000378:metabolism*; D004558:Electric Stimulation; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D007537:Isometric Contraction / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012265:Ribonucleotides / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D007328:Insulin; D009097:Multienzyme Complexes; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D019703:Calcineurin; C031143:AICA ribonucleotide; D005947:Glucose