Metabolomics as an Important Tool for Determining the Mechanisms of Human Skeletal Muscle Deconditioning

Abstract

Muscle deconditioning impairs both locomotor function and metabolic health, and is associated with reduced quality life and increased mortality rates. Despite an appreciation of the existence of phenomena such as muscle anabolic resistance, mitophagy, and insulin resistance with age and disease in humans, little is known about the mechanisms responsible for these negative traits. With the complexities surrounding these unknowns and the lack of progress to date in development of effective interventions, there is a need for alternative approaches. Metabolomics is the study of the full array of metabolites within cells or tissues, which collectively constitute the metabolome. As metabolomics allows for the assessment of the cellular metabolic state in response to physiological stimuli, any chronic change in the metabolome is likely to reflect adaptation in the physiological phenotype of an organism. This, therefore, provides a holistic and unbiased approach that could be applied to potentially uncover important novel facets in the pathophysiology of muscle decline in ageing and disease, as well as identifying prognostic markers of those at risk of decline. This review will aim to highlight the current knowledge and potential impact of metabolomics in the study of muscle mass loss and deconditioning in humans and will highlight key areas for future research.

Ageing and exercise‐induced motor unit remodelling

“…This may involve voluntary exercise, pharmaceutical intervention, exogenous hormone administration (Guo, Piasecki et al., 2021; Swiecicka et al., 2020) and/or electrical stimulation (Guo, Phillips et al., 2021). Finally, future mechanistic studies should aim to combine targeted biopsies to increase NMJ enrichment, omics‐based approaches (Alldritt et al., 2021) and in vivo electrophysiological applications to explore the ‘physiol‐omics’ of the human NMJ. Such a focus upon cellular components and signalling pathways involved in axonal sprouting could reveal targets for future therapeutics with clinical applications in populations vulnerable to muscle atrophy beyond ageing alone.…”

The muscle proteome reflects changes in mitochondrial function, cellular stress and proteolysis after 14 days of unilateral lower limb immobilization in active young men

“…Regardless, reductions in the capacity for energy production will have negative implications on other energy-dependant biological processes. It should be noted however, that our data represent protein changes within the muscle cell, but the organ systems or whole-body metabolic consequences are yet to be fully determined [ 32 ]. Although recent work has examined the plasma metabolome of older men following 7 days of post-surgery bedrest [ 33 ], the vastly different population groups prevent meaningful comparison to our work.…”

Insulin and cancer: a tangled web

“…Likely mechanisms of sarcopenia-associated insulin resistance include reduced mitochondrial function (i.e. the ability to oxidize metabolites) [ 82 , 83 ], reduced skeletal muscle mass and thus reduced skeletal muscle glucose disposal [ 53 , 84 ], as well as protein wasting that involves the release of deleterious metabolites [ 85 ] ( Figure 1 ). For example, elevated branched-chain amino acid (BCAA) concentrations are an independent predictor of type 2 diabetes risk and incidence [ 86–89 ], and considering that BCAAs are essential amino acids that cannot be synthesized de novo , BCAA concentrations in plasma must reflect either dietary intake and/or an imbalance between skeletal muscle protein anabolism and skeletal muscle protein catabolism.…”