Molecular aging and rejuvenation of human muscle stem cells

Very little remains known about the regulation of human organ stem cells (in general, and during the aging process), and most previous data were collected in short-lived rodents. We examined whether stem cell aging in rodents could be extrapolated to genetically and environmentally variable humans. Our findings establish key evolutionarily conserved mechanisms of human stem cell aging. We find that satellite cells are maintained in aged human skeletal muscle, but fail to activate in response to muscle attrition, due to diminished activation of Notch compounded by elevated transforming growth factor beta (TGF-β)/phospho Smad3 (pSmad3). Furthermore, this work reveals that mitogen-activated protein kinase (MAPK)/phosphate extracellular signal-regulated kinase (pERK) signalling declines in human muscle with age, and is important for activating Notch in human muscle stem cells. This molecular understanding, combined with data that human satellite cells remain intrinsically young, introduced novel therapeutic targets. Indeed, activation of MAPK/Notch restored ‘youthful’ myogenic responses to satellite cells from 70-year-old humans, rendering them similar to cells from 20-year-old humans. These findings strongly suggest that aging of human muscle maintenance and repair can be reversed by ‘youthful’ calibration of specific molecular pathways

Assessment of muscle function using hybrid PET/MRI:comparison of ¹⁸F-FDG PET and T2-weighted MRI for quantifying muscle activation in human subjects

PURPOSE: The aim of this study was to determine the relationship between relative glucose uptake and MRI T (2) changes in skeletal muscles following resistance exercise using simultaneous PET/MRI scans. METHODS: Ten young healthy recreationally active men (age 21 – 28 years) were injected with (18)F-FDG while activating the quadriceps of one leg with repeated knee extension exercises followed by hand-grip exercises for one arm. Immediately following the exercises, the subjects were scanned simultaneously with (18)F-FDG PET/MRI and muscle groups were evaluated for increases in (18)F-FDG uptake and MRI T (2) values. RESULTS: A significant linear correlation between (18)F-FDG uptake and changes in muscle T (2) (R (2) = 0.71) was found. for both small and large muscles and in voxel to voxel comparisons. Despite large intersubject differences in muscle recruitment, the linear correlation between (18)F-FDG uptake and changes in muscle T (2) did not vary among subjects. CONCLUSION: This is the first assessment of skeletal muscle activation using hybrid PET/MRI and the first study to demonstrate a high correlation between (18)F-FDG uptake and changes in muscle T (2) with physical exercise. Accordingly, it seems that changes in muscle T (2) may be used as a surrogate marker for glucose uptake and lead to an improved insight into the metabolic changes that occur with muscle activation. Such knowledge may lead to improved treatment strategies in patients with neuromuscular pathologies such as stroke, spinal cord injuries and muscular dystrophies

Changes in systemic GDF15 across the adult lifespan and their impact on maximal muscle power: the Copenhagen Sarcopenia Study

Background Although growth differentiation factor 15 (GDF15) is known to increase with disease and is associated with low physical performance, the role of GDF15 in normal ageing is still not fully understood. Specifically, the influ ence of circulating GDF15 on impairments in maximal muscle power (a major contributor to functional limitations) and the underlying components has not been investigated. Methods Data from 1305 healthy women and men aged 20 to 93 years from The Copenhagen Sarcopenia Study were analysed. Circulating levels of GDF15 and markers of inflammation (tumor necrosis factor-alpha, interleukin-6, and high-sensitivity C-reactive protein) were measured by ELISA (R&D Systems) and multiplex bead-based immunoassays (Bio-Rad). Relative (normalized to body mass), allometric (normalized to height squared), and specific (normalized to leg muscle mass) muscle power were assessed by the Nottingham power rig [leg extension power (LEP)] and the 30 s sit-to-stand (STS) muscle power test. Total body fat, visceral fat, and leg lean mass were assessed by dual energy X-ray absorptiometry. Leg skeletal muscle index was measured as leg lean mass normalized to body height squared. Results Systemic levels of GDF15 increased progressively as a function of age in women (1.1 ± 0.4 pg·mL 1 ·year 1 ) and men (3.3 ± 0.6 pg·mL 1 ·year 1 ) (both P < 0.05). Notably, GDF15 increased at a faster rate from the age of 65 years in women (11.5 ± 1.2 pg·mL 1 ·year 1 , P < 0.05) and 70 years in men (19.3 ± 2.3 pg·mL 1 ·year 1 , P < 0.05), resulting in higher GDF15 levels in men compared with women above the age of 65 years (P < 0.05). Independently of age and circulatory markers of inflammation, GDF15 was negatively correlated to relative STS power (P < 0.05) but not LEP, in both women and men. These findings were mainly explained by negative associations of GDF15 with specific STS power in women and men (both P < 0.05). Conclusions A J-shaped relationship between age and systemic GDF15 was observed, with men at older age showing steeper increases and elevated GDF15 levels compared with women. Importantly, circulating GDF15 was indepen dently and negatively associated with relative STS power, supporting the potential role of GDF15 as a sensitive biomarker of frailty in older people

Relative sit-to-stand power: aging trajectories, functionally relevant cut-off points, and normative data in a large European cohort

Background A validated, standardized, and feasible test to assess muscle power in older adults has recently been re ported: the sit-to-stand (STS) muscle power test. This investigation aimed to assess the relationship between relative STS power and age and to provide normative data, cut-off points, and minimal clinically important differences (MCID) for STS power measures in older women and men. Methods A total of 9320 older adults (6161 women and 3159 men) aged 60–103 years and 586 young and middle-aged adults (318 women and 268 men) aged 20–60 years were included in this cross-sectional study. Relative (normalized to body mass), allometric (normalized to height squared), and specific (normalized to legs muscle mass) muscle power values were assessed by the 30 s STS power test. Body composition was evaluated by dual energy X-ray absorptiometry and bioelectrical impedance analysis, and legs skeletal muscle index (SMI; normalized to height squared) was calculated. Habitual and maximal gait speed, timed up-and-go test, and 6 min walking distance were col lected as physical performance measures, and participants were classified into two groups: well-functioning and mobility-limited older adults. Results Relative STS power was found to decrease between 30–50 years ( 0.05 W·kg 1 ·year 1 ; P > 0.05), 50–80 years ( 0.10 to 0.13 W·kg 1 ·year 1 ; P < 0.001), and above 80 years ( 0.07 to 0.08 W·kg 1 ·year 1 ; P < 0.001). A total of 1129 older women (18%) and 510 older men (16%) presented mobility limitations. Mobility-limited older adults were older and exhibited lower relative, allometric, and specific power; higher body mass index (BMI) and legs SMI (both only in women); and lower legs SMI (only in men) than their well-functioning coun terparts (all P < 0.05). Normative data and cut-off points for relative, allometric, and specific STS power and for BMI and legs SMI were reported. Low relative STS power occurred below 2.1 W·kg 1 in women (area under the curve, AUC, [95% confidence interval, CI] = 0.85 [0.84–0.87]) and below 2.6 W·kg 1 in men (AUC [95% CI] = 0.89 [0.87–0.91]). The age-adjusted odds ratios [95% CI] for mobility limitations in older women and men with low relative STS power were 10.6 [9.0–12.6] and 14.1 [10.9–18.2], respectively. MCID values for relative STS power were 0.33 W·kg 1 in women and 0.42 W·kg 1 in men. Conclusions Relative STS power decreased significantly after the age of 50 years and was negatively and strongly as sociated with mobility limitations. Our study provides normative data, functionally relevant cut-off points, and MCID values for STS power for their use in daily clinical practice