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
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Media type:
E-Article
Title:
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
Description:
<jats:title>Abstract</jats:title><jats:p>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 C<jats:sub>16:0</jats:sub> and C<jats:sub>18:0</jats:sub> ceramide species was detected in aged skeletal muscle. Consistently, the expression of <jats:italic>CerS1</jats:italic> and <jats:italic>CerS5</jats:italic> mRNA, encoding the ceramide synthases (CerS) with substrate preference for C<jats:sub>16:0</jats:sub> and C<jats:sub>18:0</jats:sub> acyl chains, respectively, was down‐regulated in skeletal muscle of aged mice. Similarly, an age‐dependent decline of both <jats:italic>CerS1</jats:italic> and <jats:italic>CerS5</jats:italic> mRNA expression was observed in skeletal muscle biopsies of humans. Moreover, <jats:italic>CerS1</jats:italic> and <jats:italic>CerS5</jats:italic> 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 <jats:italic>CerS</jats:italic>5 on muscle function was addressed by reversed genetic analysis using <jats:italic>CerS1</jats:italic><jats:sup>Δ/Δ</jats:sup> and <jats:italic>CerS5</jats:italic><jats:sup>Δ/Δ</jats:sup> knockout mice. Skeletal muscle from mice deficient of either <jats:italic>CerS1</jats:italic> or <jats:italic>CerS5</jats:italic> 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, <jats:italic>CerS1</jats:italic>‐ and <jats:italic>CerS5</jats:italic>‐deficient mice exhibited reduced twitch and tetanus forces of <jats:italic>musculus extensor digitorum longus</jats:italic>. 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.</jats:p>