Abstract
AMP-activated protein kinase (AMPK) is a key regulator of energy homeostasis under conditions of energy stress. Though heart is one of the most energy requiring organs and depends on a perfect match of energy supply with high and fluctuating energy demand to maintain its contractile performance, the role of AMPK in this organ is still not entirely clear, in particular in a non-pathological setting. In this work, we characterized cardiomyocyte-specific, inducible AMPKα1 and α2 knockout mice (KO), where KO was induced at the age of 8 weeks, and assessed their phenotype under physiological conditions. In the heart of KO mice, both AMPKα isoforms were strongly reduced and thus deleted in a large part of cardiomyocytes already 2 weeks after tamoxifen administration, persisting during the entire study period. AMPK KO had no effect on heart function at baseline, but alterations were observed under increased workload induced by dobutamine stress, consistent with lower endurance exercise capacity observed in AMPK KO mice. AMPKα deletion also induced a decrease in basal metabolic rate (oxygen uptake, energy expenditure) together with a trend to lower locomotor activity of AMPK KO mice 12 months after tamoxifen administration. Loss of AMPK resulted in multiple alterations of cardiac mitochondria: reduced respiration with complex I substrates as measured in isolated mitochondria, reduced activity of complexes I and IV, and a shift in mitochondrial cristae morphology from lamellar to mixed lamellar-tubular. A strong tendency to diminished ATP and glycogen level was observed in older animals, 1 year after tamoxifen administration. Our study suggests important roles of cardiac AMPK at increased cardiac workload, potentially limiting exercise performance. This is at least partially due to impaired mitochondrial function and bioenergetics which degrades with age.
Highlights
Adenosine monophosphate (AMP)-activated protein kinase (AMPK) has been initially described as a key sensor and regulator of energy and nutrient signaling, participating in the maintenance of cellular energy homeostasis (Hardie et al, 1998, 2012; Viollet et al, 2010)
Immunoblot analysis confirmed an enrichment of AMPKα2 in cardiomyocytes as compared to total heart, and a large decrease of both AMPKα2 and α1 isoforms after KO induction (Figure 2B)
In absence of α subunits, β and γ cannot fold and/or form stable subcomplexes and are degraded. These data suggest that the largest portion of cardiomyocytes has lost expression of the entire AMPK heterotrimeric complex. This loss of AMPK (Figure 2A) and AMPK or ACC phosphorylation (Figure 2D) was specific to the heart, since no changes were observed in skeletal muscles
Summary
Adenosine monophosphate (AMP)-activated protein kinase (AMPK) has been initially described as a key sensor and regulator of energy and nutrient signaling, participating in the maintenance of cellular energy homeostasis (Hardie et al, 1998, 2012; Viollet et al, 2010). AMPK activation occurs by collective action of covalent and allosteric mechanisms, which involve upstream kinases (LKB1, predominant in the heart, and CaMKKβ) and phosphatases that act on T172 within the α subunit, as well as increased AMP and ADP levels (resulting from the use of ATP) that favor covalent activation, and activate via binding to the regulatory γ subunit. AMPK signaling will compensate energy deficits by stimulating production and decreasing consumption of cellular ATP. Much of this regulation targets metabolic pathways, e.g., by activation of sugar and fatty acid uptake/oxidation, or by inhibition of lipid, carbohydrate and protein synthesis. AMPK signaling acts beyond metabolic pathways via signaling at the organellar and cellular levels
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
