Cardiac hypertrophy is an adaptive response that occurs following increased stress on the heart wall, and can be caused by strenuous exercise, hypertension, heart attack or heart valve disease. In some cases, this can lead to heart failure.
Although the biological mechanism underlying cardiac hypertrophy is not fully elucidated, dysregulation of the AMPK–mTOR signalling pathway is known to play a role (Maillet et al., 2013). Hasumi et al. (2014) decided to investigate the role of FLCN in cardiac hypertrophy, given FLCN’s role in AMPK and mTOR signalling, by generating mice with both copies of FLCN specifically deleted in heart and skeletal muscle using the CKM-Cre driver mouse strain.
Mice lacking FLCN in heart and skeletal muscle had cardiac hypertrophy as shown by enlarged hearts, severe cardiac dysfunction and reduced lifespan. In vitro data from mouse embryonic fibroblasts (MEFs), showed that loss of FLCN led to increased mTOR signalling, increased protein synthesis and decreased autophagy, suggesting that dysregulated mTOR signalling may be responsible for the heart pathology in the FLCN knockout mice. In support of this hypothesis, Rapamycin treatment significantly reduced heart size and improved cardiac function.
However, mice lacking both the FLCN and the PGC1a gene showed no cardiac hypertrophy, indicating that the phenotype was mediated entirely through PGC1a. Increased PGC1a expression lead to increased mitochondrial respiration, with increased the amount of intracellular ATP, which inhibited AMPK activity, and ultimately led to mTOR dysregulation.
The results of this study correspond with those of several others. Goncharova et al. found that loss of FLCN in alveolar type II cells lead to a decrease in E-cadherin expression, reduced LKB1 signalling, and a consequent reduction in AMPK activity. Interestingly, mice lacking functional LKB1 also develop cardiac hypertrophy (Ikeda et al., 2009). Furthermore, Kumasaka et al. recently suggested that heterozygous loss of FLCN in the lung makes alveoli weaker and susceptible to mechanical stress during breathing, which may cause cysts to develop. Taken together, is it possible that reduced E‑cadherin expression and subsequent reduced AMPK activity via reduced LKB1 activity caused by FLCN depletion make cardiac and lung tissues vulnerable to mechanical stress, thus causing cardiac hypertrophy and lung cysts to develop.
Recently Yan et al. also noted increased PGC1a expression, increased mitochondrial mass, and increased ATP production in FLCN-null cells. Yan et al., however, found constitutive AMPK activity to be upstream of PGC1a hyperactivity, rather than downstream. Furthermore, conversely to the data reported here by Hasumi et al., which suggest that FLCN inhibits mTOR signalling, last year two studies reported that FLCN activates mTOR signalling at the lysosome following amino acid restimulation.
The role of FLCN in AMPK-mTOR signalling has been difficult to define, with a number of contradicting reports. While some of these differences are likely to be due to cell specific effects, due to the role of AMPK, mTOR and FLCN in energy sensing, a concerted effort to investigate different culture conditions on FLCN-null cells may also shed light on this issue. Furthermore, systematic analysis of sub-cellular FLCN localisation and which proteins FLCN interacts with in different cell types, in different sub-cellular locations and under different culture conditions will also be valuable to delineate this pathway.
Cardiac hypertrophy is not a symptom of BHD, and the mice studied by Hasumi et al. had both copies of FLCN deleted, whereas BHD patients are heterozygous for FLCN inactivation. Thus BHD patients should not be concerned about developing cardiac hypertrophy. However, it would be interesting to determine the proportion of cardiac hypertrophy patients with sporadic FLCN inactivation to assess the clinical significance of this finding.
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