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

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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

• Tipo de documento: Artigo Científico
• Fonte: Science Translational Medicine; v. 15, n. 696, p. 14-pg., 2023-05-17.

Resumo

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)

• Processo FAPESP: 19/11171-7 - Plataforma de triagem para a identificação de alvos moleculares envolvidos na homeostase mitocondrial
• Beneficiário: Tanes Imamura de Lima
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
• Processo FAPESP: 13/07607-8 - CMPO - Centro Multidisciplinar de Pesquisa em Obesidade e Doenças Associadas
• Beneficiário: Licio Augusto Velloso
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 16/23008-5 - Identificação e caracterização funcional de proteína do complexo NCoR1 associada ao controle molecular do processo de biogênese mitocondrial
• Beneficiário: Leonardo dos Reis Silveira
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 19/22512-0 - Efeitos da restrição calórica e do exercício físico sobre o mecanismo de agregação proteica no músculo esquelético
• Beneficiário: Barbara Moreira Crisol
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado