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 CerS1 Δ/Δ and CerS5 Δ/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.
Highlights
Skeletal muscle mass and strength progressively decline during aging
The most striking observation was a consistent decline of C16:0 and C18:0 Cer and sphingomy‐ elin (SM) in skeletal muscle of aged mice and a corresponding decline of CerS1 mRNA and CerS5 mRNA expression
CerS1 and CerS5 mRNA expres‐ sion declined age dependently but was associated with chronic heart failure, suggesting that age‐ and critical illness‐related changes of specific Cer species contribute to myo‐pathological disorders
Summary
Skeletal muscle mass and strength progressively decline during aging. The age‐related loss of muscle mass has been attributed to decrease in muscle fiber number and muscle fiber size (Nilwik et al, 2013). Expression of CerS1 and CerS5 mRNA was significantly reduced in skeletal muscle of old mice (Figure 1e). Mass spectrometry analysis of CerS1ΔskMuscle mice revealed muscle‐ specific down‐regulation of C18:0 Cer in skeletal muscle (Figure 4c, left), while as expected no changes in abundance of C18:0 Cer were observed in brain of these mice. Sought to assess po‐ tential functional consequences of CerS1 and CerS5 deficiencies in muscle strength of the fast‐twitch musculus extensor digitorum longus (EDL), that consists of mainly fast‐glycolytic type 2 fibers (Schiaffino & Reggiani, 2011). The impairment of muscle strength correlated well with the ca‐ liber sizes of type 2 fibers in EDL from CerS1Δ/Δ, CerS1ΔskMuscle, and CerS5Δ/Δ mice, which were significantly reduced (Figure 6c–e). In contrast to the skeletal muscle‐specific, CerS1 KO mice, CerS5Δ/Δ mice and CerS5Δ/Δ mice showed fiber type grouping, indicative for denervation processes in whole‐body knockouts
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