Impaired proteostasis is an early feature of the diabetic heart in humans and mice

Abstract

Diabetes and obesity increase cardiac lipid levels leading to cardiomyopathy and heart failure. We hypothesized that intermittent fasting would reduce cardiac lipid levels. Surprisingly, intermittent fasting increased myocardial triglyceride content, but rescued mortality and attenuated cardiomyopathy in mice overexpressing cardiomyocyte acyl-CoA synthetase 1 (MHC-ACSL1). Lipid overload caused cardiomyocyte accumulation of polyubiquitinated protein aggregates containing desmin, a scaffolding intermediate filament protein, which intermittent fasting prevented. Furthermore, intermittent fasting reversed elevated myocardial C16:0 ceramide content, and knockdown of ceramide synthase CerS5 and CerS6 reduced palmitate-induced protein aggregation, highlighting a role for C16:0 ceramides in this pathology. Conversely, impairing aggrephagy with cardiomyocyte-specific p62 ablation induced heart failure in mice fed a high-fat diet, with paradoxically reduced cardiac lipid content. Crucially, non-failing diabetic human hearts also exhibited protein aggregate pathology. Taken together, these results demonstrate that impaired proteostasis characterizes cardiomyopathy from cardiac lipid overload and identify a promising new therapeutic target for this condition.

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BibTeX RIS

BibTeX

@misc{rawnsley2026impaired,
  title = {{Impaired proteostasis is an early feature of the diabetic heart in humans and mice}},
  author = {D. R. Rawnsley and C. Zhao and X. Ma and M. Islam and J. T. Murphy and X. Guan and L. Foroughi and A. Kovacs and J. Nigro and Z. Bi and W. Navid and H. Navid and B. Razani and D. Scherr and K. Mani and K. Margulies and L. A. Cowart and S. Sedej and A. Javaheri and A. Diwan},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.01.748593},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.01.748593v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Impaired proteostasis is an early feature of the diabetic heart in humans and mice
AU  - D. R. Rawnsley
AU  - C. Zhao
AU  - X. Ma
AU  - M. Islam
AU  - J. T. Murphy
AU  - X. Guan
AU  - L. Foroughi
AU  - A. Kovacs
AU  - J. Nigro
AU  - Z. Bi
AU  - W. Navid
AU  - H. Navid
AU  - B. Razani
AU  - D. Scherr
AU  - K. Mani
AU  - K. Margulies
AU  - L. A. Cowart
AU  - S. Sedej
AU  - A. Javaheri
AU  - A. Diwan
PY  - 2026
DA  - 2026/09/01
PB  - bioRxiv
DO  - 10.64898/2026.09.01.748593
UR  - https://www.biorxiv.org/content/10.64898/2026.09.01.748593v1
AB  - Diabetes and obesity increase cardiac lipid levels leading to cardiomyopathy and heart failure. We hypothesized that intermittent fasting would reduce cardiac lipid levels. Surprisingly, intermittent fasting increased myocardial triglyceride content, but rescued mortality and attenuated cardiomyopathy in mice overexpressing cardiomyocyte acyl-CoA synthetase 1 (MHC-ACSL1). Lipid overload caused cardiomyocyte accumulation of polyubiquitinated protein aggregates containing desmin, a scaffolding intermediate filament protein, which intermittent fasting prevented. Furthermore, intermittent fasting reversed elevated myocardial C16:0 ceramide content, and knockdown of ceramide synthase CerS5 and CerS6 reduced palmitate-induced protein aggregation, highlighting a role for C16:0 ceramides in this pathology. Conversely, impairing aggrephagy with cardiomyocyte-specific p62 ablation induced heart failure in mice fed a high-fat diet, with paradoxically reduced cardiac lipid content. Crucially, non-failing diabetic human hearts also exhibited protein aggregate pathology. Taken together, these results demonstrate that impaired proteostasis characterizes cardiomyopathy from cardiac lipid overload and identify a promising new therapeutic target for this condition.
ER  -

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