Targeting the energy guardian AMPK: another avenue for treating cardiomyopathy?

Abstract

5'-AMP-activated protein kinase (AMPK) is a pivotal regulator of endogenous defensive molecules in various pathological processes. The AMPK signaling regulates a variety of intracellular intermedial molecules involved in biological reactions, including glycogen metabolism, protein synthesis, and cardiac fibrosis, in response to hypertrophic stimuli. Studies have revealed that the activation of AMPK performs a protective role in cardiovascular diseases, whereas its function in cardiac hypertrophy and cardiomyopathy remains elusive and poorly understood. In view of the current evidence of AMPK, we introduce the biological information of AMPK and cardiac hypertrophy as well as some upstream activators of AMPK. Next, we discuss two important types of cardiomyopathy involving AMPK, RKAG2 cardiomyopathy, and hypertrophic cardiomyopathy. Eventually, therapeutic research, genetic screening, conflicts, obstacles, challenges, and potential directions are also highlighted in this review, aimed at providing a comprehensive understanding of AMPK for readers.

Keywords: AMP; Cardiomyocyte; Glycogen storage; Metformin.

Fig. 1

Structure of AMPK subunits. AMPK is a heterotrimeric complex of α, β, and γ subunits. The main functions are catalysis, regulation, and conjunction in α, β, and γ subunits, respectively. The α subunit is composed of a kinase domain, an auto-inhibitor domain (AID), and a α-subunit carboxy-terminal domain (α-CTD). The β subunit consists of β-CTD and CBM and functions as the ‘bridge’ between the α and the γ subunits via β-CTD. The γ subunit has N-terminal domain (NTD) and four tandem repeats of cystathionine β synthase (CBS) to form Bateman domains

Fig. 2

Activity of AMPK heterotrimeric complex. Special site and upstream pharmacologic agonist can regulate the activity of AMPK. Phosphorylation of ST loop suppresses the connecting of agonists to AMPK and downregulates AMPK activity. AMP and phosphorylation of Thr site can enhance the activity of AMPK to >10-fold and >100-fold than basis, respectively

Fig. 3

Regulation of AMPK in cardiomyopathy. Cardiac hypertrophy is characterized by increased protein synthesis, glucose storage, fibrosis, and impaired cardiac contraction. AMPK is a key regulator for suppressing hypertrophic stimuli and maintaining the integrity of cardiomyocytes. The activation of AMPK is able to inhibit protein synthesis, glucose storage, and fibrosis, and to improve cardiac fibrosis to ameliorate hypertrophic process and keep a better cardiac function

Fig. 4

Schematic of PRKAG2 cardiomyopathy and HCM. PRKAG2 cardiomyopathy and HCM are two different cardiomyopathy and have its own characteristic. The dominant mutation in the γ2 regulatory subunit of AMPK on chromosome 7q3 may cause PRKAG2 cardiomyopathy manifesting as glycogen overload, ventricular preexcitation, and WPWs. HCM is caused by more than 11 gene mutations and characterized with ventricular preexcitation, WPWs, sarcomeres mutation, and myofibrillar disarray, which can be attenuated by endogenous or exogenous AMPK. It is a little hard to distinguish PRKAG2 cardiomyopathy from HCM in clinic and sometimes need genetic screening for help