AMP-activated protein kinase : the connection between exercise and type II diabetes

Skeletal muscle insulin resistance is a hallmark feature of Type 2 diabetes. Physical exercise/muscle contraction elicits an insulin-independent increase in glucose transport and perturbation of this pathway can bypass defective insulin signaling. To date, the exercise-responsive signaling molecules governing to glucose metabolism are largely unknown. Here we evaluate the role of AMP-activated protein kinase (AMPK), a key exercise-responsive signaling kinase, by functionally dissecting its role in skeletal muscle metabolism. AMPK activity and glucose transport was determined in insulin resistant skeletal muscle from a model of obesity-induced insulin resistance to determine if contraction- and hypoxiastimulated AMPK signaling is intact in insulin resistance tissue. An isoform -specific defect in AMPK(alpha)1 activity in response to contraction was observed, which was inconsequential to glucose transport. Thus, the AMPK signaling to glucose transport is unaffected by insulin resistance.

The AMPK(gamma)3-isoform is expressed specifically in skeletal muscle of humans and rodents. The conservation of the tissue specific expression profile of the (gamma)3-isoform in skeletal muscle between humans and rodents provides a tissue specific target for activation. We identified the predominant AMPK complex expressed in skeletal muscle as alpha2beta2gamma3.

A functional dissection of the AMPK(gamma)3-isoform was performed using transgenic mice overexpressing the wild-type (Tg-Prkag3wt) or mutant (TG-Prkag3225Q) isoform or knockout (Prkag3-/-) of AMPK(gamma)3 in mice. The R225Q mutation profoundly increases glycogen content in skeletal muscle, whereas overexpression of the wild-type AMPK(gamma)3-isoforni was without effect. Ablation of the (gamma)3isoform led to a mild reduction in glycogen content in glycolytic skeletal muscle. A paramount finding through studies in functional genomics is the R225Q mutation protects against the development of diet-induced insulin resistance. Tg-Prkag3225Q mice have increased lipid oxidation in the presence of increased lipid supply, which attenuates the expected accumulation of IMTG content and protects against skeletal muscle insulin resistance.

Activation of AMPK constitutes a possible mechanism regulating the adaptation of skeletal muscle to exercise. A profound enhancement in the induction of lipid oxidative capacity, both metabolically and transcriptionally was observed as a result of the R225Q mutation. In addition, TgPrkag3225Q mice have an apparent glycogen feedback control on AMPK activity. These responses are lost by ablation of the AMPK(gamma)3-isoform.

In conclusion, activation of AMPK can bypass defects in insulin signaling and improve glucose homeostasis in diabetes. The AMPK(gamma)3-isoform offers a tissue-specific entry-point into the regulation of glucose and lipid metabolism. Moreover, the AMPK(gamma)3 R225Q mutation greatly enhances the ability of skeletal muscle to respond to metabolic challenges such as fasting and exercise. Moreover, activation of AMPK through AMPK(gamma)3 alteration is beneficial in preventing insulin resistance and enhancing exercise responses. Not only does the AMPK(gamma)3-isoform provide tissue specific targeting for the treatment of insulin resistance, it may provide a mechanism of activation for sports enhancement.

List of scientific papers

I. Barnes BR, Ryder JW, Steiler TL, Fryer LG, Carling D, Zierath JR (2002). "Isoform-specific regulation of 5 AMP-activated protein kinase in skeletal muscle from obese Zucker (fa/fa) rats in response to contraction. " Diabetes 51(9): 2703-8
https://pubmed.ncbi.nlm.nih.gov/12196462

II. Mahlapuu M, Johansson C, Lindgren K, Hjalm G, Barnes BR, Krook A, Zierath JR, Andersson L, Marklund S (2004). "Expression profiling of the gamma-subunit isoforms of AMP-activated protein kinase suggests a major role for gamma3 in white skeletal muscle. " Am J Physiol Endocrinol Metab 286(2): E194-200. Epub 2003 Oct 14
https://pubmed.ncbi.nlm.nih.gov/14559719

III. Barnes BR, Marklund S, Steiler TL, Walter M, Hjalm G, Amarger V, Mahlapuu M, Leng Y, Johansson C, Galuska D, Lindgren K, Abrink M, Stapleton D, Zierath JR, Andersson L (2004). "The 5-AMP-activated protein kinase gamma3 isoform has a key role in carbohydrate and lipid metabolism in glycolytic skeletal muscle. " J Biol Chem 279(37): 38441-7. Epub 2004 Jul 06
https://pubmed.ncbi.nlm.nih.gov/15247217

IV. Barnes BR, Glund S, Hjalm G, Andersson L, Zierath JR (2004). "The 5-AMP-activated protein kinase gamma3 isoform plays a crucial role in post-exercise metabolic response." (Submitted)

V. Barnes BR, Long YC, Steiler TL, Leng Y, Galuska D, Wojtaszewski J, Andersson L, Zierath JR (2004). "Mutation of the 5-AMP-activated protein kinase gamma3 isoform enhances exercise-induced metabolic and gene regulatory responses in skeletal muscle." (Manuscript)