BSCL2/Seipin deficiency in hearts causes cardiac energy deficit and dysfunction via inducing excessive lipid catabolism

Abstract

Background Heart failure (HF) is one of the leading causes of death worldwide and is associated with cardiac metabolic perturbations. Human Type 2 Berardinelli‐Seip Congenital Lipodystrophy (BSCL2) disease is caused by mutations in the BSCL2 gene. Global lipodystrophic Bscl2 −/− mice exhibit hypertrophic cardiomyopathy with reduced cardiac steatosis. Whether BSCL2 plays a direct role in regulating cardiac substrate metabolism and/or contractile function remains unknown. Methods We generated mice with cardiomyocyte‐specific deletion of Bscl2 ( Bscl2 cKO ) and studied their cardiac substrate utilisation, bioenergetics, lipidomics and contractile function under baseline or after either a treatment regimen using fatty acid oxidation (FAO) inhibitor trimetazidine (TMZ) or a prevention regimen with high‐fat diet (HFD) feeding. Mice with partial ATGL deletion and cardiac‐specific deletion of Bscl2 were also generated followed by cardiac phenotyping. Results Different from hypertrophic cardiomyopathy in Bscl2 −/− mice, mice with cardiac‐specific deletion of Bscl2 developed systolic dysfunction with dilation. Myocardial BSCL2 deletion led to elevated ATGL expression and FAO along with reduced cardiac lipid contents. Cardiac dysfunction in Bscl2 cKO mice was independent of mitochondrial dysfunction and oxidative stress, but associated with decreased metabolic reserve and ATP levels. Importantly, cardiac dysfunction in Bscl2 cKO mice could be partially reversed by FAO inhibitor TMZ, or prevented by genetic abolishment of one ATGL allele or HFD feeding. Lipidomic analysis further identified markedly reduced glycerolipids, glycerophospholipids, NEFA and acylcarnitines in Bscl2 cKO hearts, which were partially normalised by TMZ or HFD. Conclusions We identified a new form of cardiac dysfunction with excessive lipid utilisation which ultimately causes cardiac substrate depletion and bioenergetics failure. Our findings also uncover a crucial role of BSCL2 in controlling cardiac lipid catabolism and contractile function and provide novel insights into metabolically treating energy‐starved HF using FAO inhibitor or HFD.

Myocardin reverses insulin resistance and ameliorates cardiomyopathy by increasing IRS-1 expression in a murine model of lipodystrophy caused by adipose deficiency of vacuolar H+-ATPase V0d1 subunit

“…Here, we found that Atp6v0d1 AKO mice display a similar developmental trajectory of cardiomyopathy to that observed in Bscl2 -/- mice, the most widely used animal model for studying lipodystrophy-related cardiomyopathy recapitulating human type 2 Berardinelli-Seip congenital lipodystrophy (BSCL2) disease, which progresses from compensated cardiac hypertrophy to heart failure 40 . Yet, loss of BSCL2 specifically in the myocardium also leads to the onset of cardiomyopathy 41 , adding the complexity of this model as whether dysfunctional AT or altered cardiac functions as the direct cause for cardiomyopathy. Moreover, the cardiomyopathy in Atp6v0d1 AKO mice can be rescued by increasing systemic insulin sensitivity with Rosiglitazone ( Figure S6 ), similar to that observed in Bscl2 -/- mice 42 , demonstrating the prominent feature of lipodystrophy cardiomyopathy that had been observed in the well-established Bscl2 -/- lipodystrophy mice.…”

Host genetic susceptibility underlying SARS-CoV-2-associated Multisystem Inflammatory Syndrome in Brazilian Children

“…The interaction of lipid droplets with phagosomes containing pathogens occurs in response to infections, influencing the outcome or survival of the pathogen within host cells (Melo and Dvorak 2012 ). Thus, seipin could interfere in the capacity of macrophages to respond to pathogens through the lipid droplet metabolism and one-third of patients with congenital generalised lipodystrophy, a recessive condition caused by BSCL2 variants, died of infectious disease (Zhou et al 2022 ). Although patient EXOC18 had no noticed lipodystrophy previous to MIS-C, BSCL2 variants are also described in dominant clinical conditions (OMIM), which could explain the higher susceptibility to MIS-C.…”

“…Although patient EXOC18 had no noticed lipodystrophy previous to MIS-C, BSCL2 variants are also described in dominant clinical conditions (OMIM), which could explain the higher susceptibility to MIS-C. Furthermore, global lipodystrophic Bscl2 −/−mice exhibit hypertrophic cardiomyopathy with reduced cardiac steatosis, and mice with cardiac-specific deletion of Bscl2 developed systolic dysfunction with dilation, through excessive lipid catabolism (Zhou et al 2022 ). Curiously, patient EXOC18 presented Reentrant Supraventricular Tachycardias (RST) phenotype during the follow- up.…”

Myocardial protection by desflurane: from basic mechanisms to clinical applications

“…2 Not only is glucose aerobically oxidized more efficiently than FFAs, in metabolites compared with fatty acid–induced myocardial diastolic dysfunction, glucose maintains cellular homeostasis and reduces myocardial injury after ischemia. 3 Myocardium is rich in mitochondria, which determine cell death and survival through multiple pathways.…”