Abstract
Sarcopenia is the age-related loss of skeletal muscle mass, strength and function, which may be accelerated during periods of physical inactivity. Declines in skeletal muscle and functionality not only impacts mobility but also increases chronic disease risk, such as type 2 diabetes. The aim of this study was to measure adaptive metabolic responses to acute changes in habitual activity in a cohort of overweight, pre-diabetic older adults (age = 69 ± 4 years; BMI = 27 ± 4 kg/m2, n = 17) when using non-targeted metabolite profiling by multisegment injection-capillary electrophoresis-mass spectrometry. Participants completed two weeks of step reduction (<1000 steps/day) followed by a two week recovery period, where fasting plasma samples were collected at three time intervals at baseline, after step reduction and following recovery. Two weeks of step reduction elicited increases in circulatory metabolites associated with a decline in muscle energy metabolism and protein degradation, including glutamine, carnitine and creatine (q < 0.05; effect size > 0.30), as well as methionine and deoxycarnitine (p < 0.05; effect size ≈ 0.20) as compared to baseline. Similarly, decreases in uremic toxins in plasma that promote muscle inflammation, indoxyl sulfate and hippuric acid, as well as oxoproline, a precursor used for intramuscular glutathione recycling, were also associated with physical inactivity (p < 0.05; effect size > 0.20). Our results indicate that older persons are susceptible to metabolic perturbations due to short-term step reduction that were not fully reversible with resumption of normal ambulatory activity over the same time period. These plasma biomarkers may enable early detection of inactivity-induced metabolic dysregulation in older persons at risk for sarcopenia not readily measured by current imaging techniques or muscle function tests, which is required for the design of therapeutic interventions to counter these deleterious changes in support of healthy ageing.
Highlights
Sarcopenia is the progressive, degenerative decline in skeletal muscle mass, function and strength and is measurable after the fifth decade of life [1,2,3] affecting 5–13% of 60–70 year olds and up to 50%of those aged 80 years and older [4]
Multiplexed separations based on MSI-capillary electrophoresis (CE)-MS offer a high throughput platform for biomarker discovery in metabolomics that is optimal for analysis of mass or volume-restricted biological specimens ranging from dried blood spot punches, infant sweat specimens to skeletal muscle tissue biopsies [19,20,21,22]
Major improvements in sample throughput are achieved without added infrastructure costs or complicated column switching programs, which allows for stringent quality control (QC) and batch correction [23]
Summary
Sarcopenia is the progressive, degenerative decline in skeletal muscle mass, function and strength and is measurable after the fifth decade of life [1,2,3] affecting 5–13% of 60–70 year olds and up to 50%of those aged 80 years and older [4]. Multiple factors contribute to sarcopenia, including age-related biological changes (e.g., chronic inflammation, oxidative stress, hormonal alterations), malnutrition (e.g., decreased protein and total caloric intake), as well as physical inactivity [1,4,5]. All these stressors contribute to profound physiological and morphological changes in skeletal muscle structure and function, leading to a loss in functionality and independence [2,6] with greater physical frailty [7]. The current gold-standard for diagnosis of sarcopenia relies on imaging techniques based on dual-energy X-ray absorptiometry (DXA) that provides an index of skeletal muscle mass [10]; inaccuracies have been reported when comparing data from different manufacturers/instruments [11]
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