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Genomic and proteomic profiling reveals reduced mitochondrial function and disruption of the neuromuscular junction driving rat sarcopenia

ABSTRACT: Molecular mechanisms underlying sarcopenia, the age-related loss of skeletal muscle mass and function, remain unclear. To identify molecular changes that correlated best with sarcopenia and might contribute to its pathogenesis, we determined global gene expression profiles in muscles of rats aged 6, 12, 18, 21, 24, and 27 months. These rats exhibit sarcopenia beginning at 21 months. Correlation of the gene expression versus muscle mass or age changes, and functional annotation analysis identified gene signatures of sarcopenia distinct from gene signatures of aging. Specifically, mitochondrial energy metabolism (e.g., tricarboxylic acid cycle and oxidative phosphorylation) pathway genes were the most downregulated and most significantly correlated with sarcopenia. Also, perturbed were genes/pathways associated with neuromuscular junction patency (providing molecular evidence of sarcopenia-related functional denervation and neuromuscular junction remodeling), protein degradation, and inflammation. Proteomic analysis of samples at 6, 18, and 27 months confirmed the depletion of mitochondrial energy metabolism proteins and neuromuscular junction proteins. Together, these findings suggest that therapeutic approaches that simultaneously stimulate mitochondrogenesis and reduce muscle proteolysis and inflammation have potential for treating sarcopenia.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE118825 | GEO | 2018/08/21

REPOSITORIES: GEO

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Project description:Abstract Background: The prevalence of sarcopenia is increasing and effective interventions are required to prevent or reverse age-related muscle loss. However it is often challenging expensive and time-consuming to develop and test the effectiveness of such interventions. Furthermore translational animal models that adequately mimic underlying physiological pathways are scarce. Strong predictors for the incidence of sarcopenia include a sedentary life-style and malnutrition. Therefore our objective was to investigate the translational value of three potential mouse models for sarcopenia namely partial immobilized caloric restricted (CR) and a combination (immobilized & CR) model. Methods: C57BL/6J mice were calorically restricted (-40%) and/or one hindleg was immobilized for two weeks to induce loss of muscle mass and function. Muscle mass function and diameter and distribution of slow (type 1) and fast ( type 2) myofibers were compared to those of young control (4 months) and old reference mice (21 months). Transcriptome analysis of quadriceps muscle was performed to identify underlying pathways and were compared with those being expressed in aged human vastus lateralis muscle-biopsies using a meta-analysis of five different human studies. Results: Caloric restriction induced overall loss of lean body mass (-15% p<0.001) whereas immobilization decreased muscle strength (-28% p<0.001) and muscle mass of hindleg muscles specifically (on average -25% p<0.001). The proportion of slow myofibers increased with aging in mice (+5% p<0.05) and this was not recapitulated by the CR and/or immobilization models. The diameter of fast myofibers decreased with aging (-7% p<0.05) and this was mimicked by all models. Transcriptome analysis revealed that the combination of CR and immobilization recapitulated more pathways characteristic for human muscle-aging (73%) than naturally aged (21 months old) mice (45%). These pathways included critical pathways relevant for protein synthesis/ breakdown (mitochondrial) metabolism neurology and the vascular system. Conclusions: The combination model exhibits loss of both muscle mass (due to CR) and function (due to immobilization) and has a remarkable similarity with pathways underlying human sarcopenia. Our results demonstrate that naturally aging up to 21 months in mice only partially recapitulates the human pathology with fewer overlapping pathways than the combination model. These findings underline that external factors such as sedentary behavior and malnutrition are key elements of a translational mouse model and favor the combination model as a rapid model for testing the treatments against sarcopenia.

Project description:Aims: Sarcopenia is the degenerative loss of skeletal muscle mass and function at high age, which affects 5-13% of people aged 60-70 years. Although a number of factors have been linked to sarcopenia, it remains unclear what determines its emergence in some but not all individuals and there are no medical treatments available. Mice and rats are widely used as model organisms to identify factors predisposing to sarcopenia, but the extent to which age-related molecular changes in wild-type mice and rats recapitulate those occurring in humans is not known. The aim of this project was to define a conserved set of regulators of aging-related reduction in muscle function that could be targeted by future therapies. Methods: We comparatively analyzed phenotypic parameters as well as the transcriptomes of the Gastrocnemius muscle from mice, rats and humans of a wide range of ages. We further inferred computationally the transcription regulators that likely underlie the molecular changes associated with aging-related loss in muscle functionality. Results: The analysis showed that the biological age of rodents that muscle mass is a better indicator of muscle functionality than the chronological age. Investigating the molecular changes associated with the aging-related loss of muscle mass, we discovered changes in gene expression that are shared between the studied species at the level of molecular pathways rather than at the level of individual genes. Beyond the known involvement of inflammation and mitochondrial function in aging, we found that the transcription regulators SPIB, ESRRB and YY1/YY2 consistently underlie aging-related molecular changes across the studied species. Conclusions: Rodents recapitulate well the molecular changes observed in human sarcopenia, but the conservation is stronger at the molecular pathway level than at the level of individual genes. Phenotypic parameters such as the muscle mass should be taken into account in stratifying samples for analyzing aging-related processes, as the chronological age is a poorer indicator of organ functionality. The shared regulators of aging-related muscle loss that we identified here can be studied further in rodent models of sarcopenia toward defining new targets for therapy in humans.

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Genomic and proteomic profiling reveals reduced mitochondrial function and disruption of the neuromuscular junction driving rat sarcopenia

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