Skeletal muscle metabolic flexibility : the roles of AMP-activated protein kinase and calcineurin

Skeletal muscle fibers differ considerably in their metabolic and physiological properties. The metabolic properties of skeletal muscle display a high degree of flexibility which adapts to various physiological demands by shifting energy substrate metabolism. Studies were conducted to evaluate the roles of AMP-activated protein kinase (AMPK) and calcineurin in the regulation of skeletal muscle metabolism.

Fasting elicited a coordinated expression of genes involved in lipid utilization and glucose metabolism in white gastrocnemius muscle from wild-type mice. The fasting-induced transcriptional responses were impaired in the AMPKgamma3 knockout (Prkag3-/-) mice. Conversely, in mice transgenic for an activating mutant form of AMPKã3(R225Q) (Tg-Prkag3225Q), an enhanced expression of several fasting-responsive metabolic genes, and a reciprocal down-regulation of glycolytic genes was observed. The results support the role of AMPKã3 subunit in the coordinated expression of fasting-responsive metabolic genes in skeletal muscle.

Exercise stimulated glucose uptake in EDL muscles from wild-type, Tg-Prkag3225Q and Prkag3-/ mice to the same degree. In Tg-Prkag3225Q mice, elevated acetyl-CoA carboxylase phosphorylation, enhanced intramuscular triglyceride utilization and metabolic gene expression was observed after exercise. Conversely, an impaired gene expression was seen in the Prkag3-/- mice. Thus, the AMPKã3 subunit is dispensable for exercise-stimulated glucose transport and the mutant AMPKã3(R225Q) subunit promotes metabolic and gene expression adaptations in response to exercise.

Enhanced insulin-, but suppressed AICAR-induced glucose uptake was observed in EDL muscles from transgenic mice expressing an activated form of the calcium/calmodulin dependent protein phosphatase calcineurin (MCK-CnA*). Impaired AMPK-activated glucose uptake was associated with a decrease in the expression of the AMPKã3 subunit. Contractioninduced glucose uptake however was unaltered in MCK-CnA* mice, despite a decrease in contraction-induced AMPK phosphorylation. Therefore, calcineurin-induced skeletal muscle remodeling altered AMPK-activated glucose uptake.

An enhanced glucose incorporation into glycogen and a reciprocal suppression of glucose oxidation was seen in the EDL muscle from MCK-CnA* mice. These changes were accompanied by an increase in lipid oxidation and lactate release. The alterations in glucose partitioning were supported by a coordinated decrease in glycolytic genes and an elevation in Pdk4 expression. Consistent with the increase in lipid oxidation, expression lipid metabolic and mitochondrial genes were activated in EDL muscle from MCK-CnA* mice, concomitant with an induction of several transcription regulators including PPARá, PPARä and PGC1á. Therefore, calcineurin altered skeletal muscle metabolism via coordinated changes in gene expression.

In conclusion, AMPK regulates skeletal muscle lipid and glucose metabolism, as well as gene regulatory responses to fasting and exercise. Calcineurin-mediated skeletal muscle remodeling alters the expression of AMPK subunits and AMPK-mediated glucose uptake. Furthermore, calcineurin alters lipid and glucose metabolism in skeletal muscle via coordinated changes in gene expression program. Therefore, the flexibility of lipid and glucose utilization in skeletal muscle is not only regulated at the level of covalent and allosteric modifications, but the reciprocity is also conserved at transcriptional level.

List of scientific papers

I. Long YC, Barnes BR, Mahlapuu M, Steiler TL, Martinsson S, Leng Y, Wallberg-Henriksson H, Andersson L, Zierath JR (2005). "Role of AMP-activated protein kinase in the coordinated expression of genes controlling glucose and lipid metabolism in mouse white skeletal muscle." Diabetologia 48(11): 2354-64. Epub 2005 Oct 20
https://pubmed.ncbi.nlm.nih.gov/16237515

II. Barnes BR, Long YC, Steiler TL, Leng Y, Galuska D, Wojtaszewski JF, Andersson L, Zierath JR (2005). "Changes in exercise-induced gene expression in 5-AMP-activated protein kinase gamma3-null and gamma3 R225Q transgenic mice." Diabetes 54(12): 3484-9
https://pubmed.ncbi.nlm.nih.gov/16306365

III. Ryder JW, Long YC, Nilsson E, Mahlapuu M, Zierath JR (2005). "Effects of calcineurin activation on insulin-, AICAR- and contraction-induced glucose transport in skeletal muscle." J Physiol 567(Pt 2): 379-86. Epub 2005 Jun 23
https://pubmed.ncbi.nlm.nih.gov/15975979

IV. Long YC, Glund S, Garcia-Roves PM, Zierath JR (2007). "Calcineurin regulates skeletal muscle metabolism via coordinated changes in gene expression." J Biol Chem 282(3): 1607-14. Epub 2006 Nov 15
https://pubmed.ncbi.nlm.nih.gov/17107952