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Aging Cell. 2019 Nov 6:e13049. doi: 10.1111/acel.13049. [Epub ahead of print]

A tissue-specific screen of ceramide expression in aged mice identifies ceramide synthase-1 and ceramide synthase-5 as potential regulators of fiber size and strength in skeletal muscle.

Author information

1
Institute for Medical Microbiology, Immunology and Hygiene, University Hospital Cologne, Cologne, Germany.
2
Cologne Cluster of Excellence on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany.
3
Department of Neuropathology, Faculty of Medicine, University of Cologne, Cologne, Germany.
4
Department of Medicine, University of Leipzig, Leipzig, Germany.
5
Department of Cardiology (Campus Virchow Klinikum), German Centre for Cardiovascular Research, Berlin, Germany.
6
BIH Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Berlin, Germany.
7
Division of Cardiology and Metabolism, Department of Cardiology (Campus Virchow Klinikum), Charité Universitätsmedizin Berlin, Berlin, Germany.
8
Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Berlin, Germany.
9
Institute of Physiology I, Medical Faculty, University of Bonn, Bonn, Germany.
10
Center for Molecular Medicine Cologne (CMMC), Cologne, Germany.

Abstract

Loss of skeletal muscle mass is one of the most widespread and deleterious processes in aging humans. However, the mechanistic metabolic principles remain poorly understood. In the framework of a multi-organ investigation of age-associated changes of ceramide species, a unique and distinctive change pattern of C16:0 and C18:0 ceramide species was detected in aged skeletal muscle. Consistently, the expression of CerS1 and CerS5 mRNA, encoding the ceramide synthases (CerS) with substrate preference for C16:0 and C18:0 acyl chains, respectively, was down-regulated in skeletal muscle of aged mice. Similarly, an age-dependent decline of both CerS1 and CerS5 mRNA expression was observed in skeletal muscle biopsies of humans. Moreover, CerS1 and CerS5 mRNA expression was also reduced in muscle biopsies from patients in advanced stage of chronic heart failure (CHF) suffering from muscle wasting and frailty. The possible impact of CerS1 and CerS5 on muscle function was addressed by reversed genetic analysis using CerS1Δ/Δ and CerS5Δ/Δ knockout mice. Skeletal muscle from mice deficient of either CerS1 or CerS5 showed reduced caliber sizes of both slow (type 1) and fast (type 2) muscle fibers, fiber grouping, and fiber switch to type 1 fibers. Moreover, CerS1- and CerS5-deficient mice exhibited reduced twitch and tetanus forces of musculus extensor digitorum longus. The findings of this study link CerS1 and CerS5 to histopathological changes and functional impairment of skeletal muscle in mice that might also play a functional role for the aging skeletal muscle and for age-related muscle wasting disorders in humans.

KEYWORDS:

CerS1; CerS5; aging; ceramide synthases; skeletal muscle myopathy

PMID:
31692231
DOI:
10.1111/acel.13049
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