Inhibiting de novo ceramide synthesis restores mitochondrial and protein homeostasis in muscle aging

Author(s):Show less -

Lima, Tanes I. ; Laurila, Pirkka-Pekka ; Wohlwend, Martin ; Morel, Jean David ; Goeminne, Ludger J. E. ; Li, Hao ; Romani, Mario ; Li, Xiaoxu ; Oh, Chang-Myung ; Park, Dohyun ; Rodriguez-Lopez, Sandra ; Ivanisevic, Julijana ; Gallart-Ayala, Hector ; Crisol, Barbara ; Delort, Florence ; Batonnet-Pichon, Sabrina ; Silveira, Leonardo R. ; Venkata, Lakshmi Sankabattula Pavani Veera ; Padala, Anil K. ; Jain, Suresh ; Auwerx, Johan

• Document type: Journal article
• Source: Science Translational Medicine; v. 15, n. 696, p. 14-pg., 2023-05-17.

Abstract

Disruption of mitochondrial function and protein homeostasis plays a central role in aging. However, how these processes interact and what governs their failure in aging remain poorly understood. Here, we showed that cer- amide biosynthesis controls the decline in mitochondrial and protein homeostasis during muscle aging. Anal- ysis of transcriptome datasets derived from muscle biopsies obtained from both aged individuals and patients with a diverse range of muscle disorders revealed that changes in ceramide biosynthesis, as well as disturbances in mitochondrial and protein homeostasis pathways, are prevalent features in these conditions. By performing targeted lipidomics analyses, we found that ceramides accumulated in skeletal muscle with increasing age across Caenorhabditis elegans, mice, and humans. Inhibition of serine palmitoyltransferase (SPT), the rate -lim- iting enzyme of the ceramide de novo synthesis, by gene silencing or by treatment with myriocin restored pro- teostasis and mitochondrial function in human myoblasts, in C. elegans, and in the skeletal muscles of mice during aging. Restoration of these age-related processes improved health and life span in the nematode and muscle health and fitness in mice. Collectively, our data implicate pharmacological and genetic suppression of ceramide biosynthesis as potential therapeutic approaches to delay muscle aging and to manage related pro- teinopathies via mitochondrial and proteostasis remodeling. (AU)

• FAPESP's process: 19/11171-7 - Screening platform for the identification of molecular targets involved in mitochondrial homeostasis
• Grantee: Tanes Imamura de Lima
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center
• Grantee: Licio Augusto Velloso
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 16/23008-5 - Identification and functional characterization of protein bound to NCoR1 complex and associated with molecular control of mitochondrial biogenesis process
• Grantee: Leonardo dos Reis Silveira
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 19/22512-0 - Effects of calorie restriction and exercise in the skeletal muscle protein aggregration
• Grantee: Barbara Moreira Crisol
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate