Adaptation of skeletal muscle metabolic profile in response to Bed Rest

Muscle disuse is well known to be one of the causes of muscle atrophy and it can be experienced in a different number of conditions: injury, illness, microgravity in spaceflight and ageing, among others. While the main features of muscle atrophy like the reduced cross-sectional area of muscle fibers are well understood, less is known about the metabolic profile of subjects undergoing this condition. In addition, there is a need for novel biomarkers that can reflect the process of muscle disuse and can be used to monitor the effectiveness of countermeasures against disuse atrophy. Here we investigated the serum and skeletal muscle metabolic profile of ten participants subjected to nine days of Bed Rest (BR), an important human model of muscle disuse in order to find the metabolites that change in response to bed rest and that are common to serum and muscle. First, the single muscle fiber cross-sectional area (CSA) measurement of skeletal muscle biopsies collected before bed rest (T0) and after nine days of bed rest (T9) revealed a trend to 15% reduction in type II fibres, suggesting the presence of muscle atrophy. Afterwards, the Nuclear magnetic Resonance (NMR) investigation of the skeletal muscle metabolic profile highlighted a series of metabolites involved in the biochemical response to bed rest conditions. Interestingly, these metabolites start to change early with disuse and particularly change linearly with the progression of disuse. Indeed, Glutamine, ATP, Carnitine, Phosphocreatine, Creatine, Taurine, and myo-Inositol are up-regulated in response to bed rest conditions for five days (T5) and nine days (T9). Finally, the same analysis performed on serum samples obtained at different time points showed a series of discriminant metabolites of muscle disuse because of their presence one day and two days before bed rest (T0-1, T0-2) and of their down-regulation starting from five days of bed rest: they are Acetate, Betaine, Glucose and Glycerol. In contrast, Aspartate, Asparagine, Phosphocreatine, Alanine and Glutamate were found up-regulated in response to bed rest starting from five days of muscle disuse. Some of the metabolites found both in skeletal muscle and serum belong to the class of amino acids, indicating a shift of protein turnover in favor of protein degradation, which is characteristic of the condition of muscle disuse. Furthermore, the fact that Phosphocreatine was found to be up-regulated both in the skeletal muscle and in serum in response to muscle disuse suggests its muscle origin. Overall, the study allowed to (i) collocate subjects undergoing muscle disuse in different classes based on their metabolic profile; (ii) identify the subset of metabolites responsible for the discrimination of subject classes; (iii) point out potential biomarkers of muscle disuse which can be easily measurable in subject’s serum.