Increased α2 Subunit–Associated AMPK Activity and
            <i>PRKAG2</i>
            Cardiomyopathy

Ahmad, Ferhaan; Arad, Michael; Musi, Nicolas; He, Hui; Wolf, Cordula M.; Branco, Dorothy; Perez‐Atayde, Antonio R.; Stapleton, David; Bali, Deeksha; Xing, Yonglei; Tian, Rong; Goodyear, Laurie J.; Berul, Charles I.; Ingwall, Joanne S.; Seidman, Christine E.

doi:10.1161/circulationaha.105.550806

Cited by 84 publications

(83 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[28][29][30] Accordingly, the constitutive activation of AMPK via mutations in the g2 and g3 subunits has been associated with glycogen accumulation in the skeletal and cardiac muscles of pigs and mice. [30][31][32][33][34][35][36] In agreement, and similarly to what we have reported, 14 yeast snf1 mutants display decreased levels of glycogen as compared to the control. 37 Importantly, whether the osmotic stress-dependent acute activation of AMPK leads to the activation of glycogen phosphorylase is still not clear and needs further investigation.…”

Section: The Paradoxical Role Of Ampk In Glycogen Metabolismsupporting

confidence: 88%

Glycogen: A must have storage to survive stressful emergencies

Possik

Pause

2016

Worm

View full text Add to dashboard Cite

Mechanisms of adaptation to acute changes in osmolarity are fundamental for life. When exposed to hyperosmotic stress, cells and organisms utilize conserved strategies to prevent water loss and maintain cellular integrity and viability. The production of glycerol is a common strategy utilized by the nematode Caenorhabditis elegans (C. elegans) and many other organisms to survive hyperosmotic stress. Specifically, the transcriptional upregulation of glycerol-3-phosphate dehydrogenase, a rate-limiting enzyme in the production of glycerol, has been previously implicated in many model organisms. However, what fuels this massive and rapid production of glycerol upon hyperosmotic stress has not been clearly elucidated. We have recently discovered an AMPK-dependent pathway that mediates hyperosmotic stress resistance in C. elegans. Specifically, we demonstrated that the chronic activation of AMPK leads to glycogen accumulation, which under hyperosmotic stress exposure, is rapidly degraded to mediate glycerol production. Importantly, we demonstrate that this strategy is utilized by flcn-1 mutant C. elegans nematodes in an AMPKdependent manner. FLCN-1 is the worm homolog of the human renal tumor suppressor Folliculin (FLCN) responsible for the Birt-Hogg-Dub e neoplastic syndrome. Here, we comment on the dual role for glycogen in stress resistance: it serves as an energy store and a fuel for osmolyte production. We further discuss the potential utilization of this mechanism by organisms in general and by human cancer cells in order to survive harsh environmental conditions and notably hyperosmotic stress.

show abstract

Section: The Paradoxical Role Of Ampk In Glycogen Metabolismsupporting

confidence: 88%

Glycogen: A must have storage to survive stressful emergencies

Possik

Pause

2016

Worm

View full text Add to dashboard Cite

show abstract

“…This is not inconsistent with the literature because it is still controversial whether the activation of AMPK contributes to the various effects of life-long CR (22). Alterations in cardiac AMPK activity are reportedly associated with cardiac hypertrophy, cardiomyopathy, and Wolf-Parkinson-White syndrome (4,19), but CR does not induce any pathological cardiac phenotype. Our results suggest that different mechanisms are involved in the cardioprotection afforded by prolonged versus short-term CR.…”

Section: Effect Of Cr On Myocardial Ischemia-reperfusion Injury and Ipcmentioning

confidence: 79%

Impact of 6-mo caloric restriction on myocardial ischemic tolerance: possible involvement of nitric oxide-dependent increase in nuclear Sirt1

Shinmura

Tamaki

Bolli

2008

American Journal of Physiology-Heart and Circulatory Physiology

114

View full text Add to dashboard Cite

Ischemic tolerance decreases with aging, and the cardioprotective effect of ischemic preconditioning (IPC) is impaired in middle-aged animals. We have demonstrated that short-term caloric restriction (CR) improves myocardial ischemic tolerance in young and old animals via the activation of adiponectin-AMP-activated protein kinase (AMPK)-mediated signaling. However, it is unknown whether prolonged CR confers cardioprotection in a similar manner. Furthermore, little is known regarding the myocardial expression of silent information regulator 1 (Sirt1; which reportedly mediates various aspects of the CR response) with prolonged CR. Thus, 6-mo-old male Fischer-344 rats were randomly divided into ad libitum (AL) and CR groups. Six months later, isolated perfused hearts were subjected to 25 min of global ischemia followed by 120 min of reperfusion with or without IPC. CR improved the recovery of left ventricular function and reduced infarct size after ischemiareperfusion and restored the IPC effect. Serum adiponectin levels increased, but myocardial levels of total and phosphorylated AMPK did not change with prolonged CR. Total levels of Sirt1 did not change with CR; however, in the nuclear fraction, CR significantly increased Sirt1 and decreased acetyl-histone H3. Eleven rats from each group were given N-nitro-L-arginine methyl ester in their drinking water for 4 wk before death. In these hearts, chronic inhibition of nitric oxide synthase prevented the increase in nuclear Sirt1 content by CR and abrogated CR-induced cardioprotection. These results demonstrate that 1) prolonged CR improves myocardial ischemic tolerance and restores the IPC effect in middle-aged rats and 2) CR-induced cardioprotection is associated with a nitric oxidedependent increase in nuclear Sirt1 content. aging; myocardial ischemia; nutrition; preconditioning; reperfusion injury; silent information regulator 1

show abstract

“…One of the major responses of the heart to biomechanical stress and pathological stimuli is to undergo cardiac hypertrophy, an increase in the thickness of the cardiac ventricular wall (8,9). Initially, cardiac hypertrophy is an adaptive response that maintains cardiac output in the face of increased workload.…”

Section: Introductionmentioning

confidence: 99%

Cardiomyocyte-enriched protein CIP protects against pathophysiological stresses and regulates cardiac homeostasis

Huang¹,

Kataoka²,

Chen³

et al. 2015

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

ResultsLoss of CIP accelerates the progress from hypertrophy to heart failure during cardiac remodeling. We and others have previously identified a cardiac ISL1-interacting protein (CIP, also identified and referred to as MLIP [muscle-enriched A-type lamin-interacting protein]) (11,12). CIP is specifically expressed in embryonic and adult mouse myocytes and is highly conserved between mouse and human. We asked whether the expression of this gene is correlated with human cardiomyopathy. Indeed, we found that CIP transcripts were significantly reduced in the hearts of patients with dilated cardiomyopathy ( Figure 1A and Supplemental Table Cardiomyopathy is a common human disorder that is characterized by contractile dysfunction and cardiac remodeling. Genetic mutations and altered expression of genes encoding many signaling molecules and contractile proteins are associated with cardiomyopathy; however, how cardiomyocytes sense pathophysiological stresses in order to then modulate cardiac remodeling remains poorly understood. Here, we have described a regulator in the heart that harmonizes the progression of cardiac hypertrophy and dilation. We determined that expression of the myocyte-enriched protein cardiac ISL1-interacting protein (CIP, also known as MLIP) is reduced in patients with dilated cardiomyopathy. As CIP is highly conserved between human and mouse, we evaluated the effects of CIP deficiency on cardiac remodeling in mice. Deletion of the CIP-encoding gene accelerated progress from hypertrophy to heart failure in several cardiomyopathy models. Conversely, transgenic and AAV-mediated CIP overexpression prevented pathologic remodeling and preserved cardiac function. CIP deficiency combined with lamin A/C deletion resulted in severe dilated cardiomyopathy and cardiac dysfunction in the absence of stress. Transcriptome analyses of CIP-deficient hearts revealed that the p53-and FOXO1-mediated gene networks related to homeostasis are disturbed upon pressure overload stress. Moreover, FOXO1 overexpression suppressed stress-induced cardiomyocyte hypertrophy in CIP-deficient cardiomyocytes. Our studies identify CIP as a key regulator of cardiomyopathy that has potential as a therapeutic target to attenuate heart failure progression.

show abstract

Increased α2 Subunit–Associated AMPK Activity and PRKAG2 Cardiomyopathy

Cited by 84 publications

References 33 publications

Glycogen: A must have storage to survive stressful emergencies

Glycogen: A must have storage to survive stressful emergencies

Impact of 6-mo caloric restriction on myocardial ischemic tolerance: possible involvement of nitric oxide-dependent increase in nuclear Sirt1

Cardiomyocyte-enriched protein CIP protects against pathophysiological stresses and regulates cardiac homeostasis

Contact Info

Product

Resources

About