Increased alpha2 subunit-associated AMPK activity and PRKAG2 cardiomyopathy

Area of Science:

• Biochemistry
• Cardiology
• Genetics

Background:

• AMP-activated protein kinase (AMPK) regulatory gamma2 subunit (PRKAG2) mutations are linked to human cardiomyopathy.
• This condition involves cardiac hypertrophy, preexcitation, and glycogen deposition.
• PRKAG2 cardiomyopathy is modeled in mice overexpressing mutant PRKAG2 N488I (TGgamma2N488I).

Purpose of the Study:

• To investigate the role of alpha1 and alpha2 AMPK subunit isoforms in PRKAG2 cardiomyopathy.
• To determine if inhibiting alpha2-associated AMPK activity can ameliorate the disease phenotype.

Main Methods:

• Utilized transgenic mice overexpressing a dominant-negative alpha2 subunit (TGalpha2DN) to selectively inhibit alpha2-AMPK activity.
• Generated compound-heterozygous TGgamma2N488I/TGalpha2DN mice.
• Assessed ECG, cardiac function, morphology, exercise capacity, and cardiac glycogen content.

Main Results:

• Compound-heterozygous mice showed decreased alpha2-AMPK activity compared to TGgamma2N488I mice.
• The TGalpha2DN transgene partially or completely normalized ECG, cardiac function, morphology, and exercise capacity.
• TGgamma2N488I hearts demonstrated normal resting energy phosphates and utilized stored glycogen during exercise.

Conclusions:

• PRKAG2 N488I mutations inappropriately activate AMPK, causing glycogen accumulation and conduction system disease.
• Accumulated glycogen serves as an energy source, preserving contractile reserve during exercise.
• AMPK complexes involving the alpha2 subunit, not alpha1, are the primary mediators of PRKAG2 mutation effects.