Molecular aging and rejuvenation of human muscle stem cells

Department of Bioengineering, University of California, Berkeley, Berkeley CA, USA.
EMBO Molecular Medicine (Impact Factor: 8.25). 11/2009; 1(8-9):381-91. DOI: 10.1002/emmm.200900045
Source: PubMed

ABSTRACT 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-beta)/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.

Download full-text


Available from: Michael Kjaer, Aug 13, 2015
  • Source
    • "The primary role of the let-7 miR- NAs appears to be anti-proliferative, as observed in human cancer cells (Johnson et al., 2007; Nishino et al., 2008; Dong et al., 2010; Zhao et al., 2010; Lee et al., 2011) and in mouse neuronal stem cells (Nishino et al., 2008). The elevation of let-7 miRNAs may be responsible for the impaired ability to activate and proliferate satellite cells in the elderly skeletal muscle, therefore contributing to the attenuated skeletal muscle regenerative capacity in the elderly (Carlson et al., 2009). Accordingly, bioinformatics analysis identified cell cycle regulation and cellular growth and proliferation as the most highly ranked cellular processes likely to be regulated by the 2 let-7 miRNAs in humans. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Skeletal muscle makes up approximately 40% of the total body mass, providing structural support and enabling the body to maintain posture, to control motor movements and to store energy. It therefore plays a vital role in whole body metabolism. Skeletal muscle displays remarkable plasticity and is able to alter its size, structure and function in response to various stimuli; an essential quality for healthy living across the lifespan. Exercise is an important stimulator of extracellular and intracellular stress signals that promote positive adaptations in skeletal muscle. These adaptations are controlled by changes in gene transcription and protein translation, with many of these molecules identified as potential therapeutic targets to pharmacologically improve muscle quality in patient groups too ill to exercise. MicroRNAs (miRNAs) are recently identified regulators of numerous gene networks and pathways and mainly exert their effect by binding to their target messenger RNAs (mRNAs), resulting in mRNA degradation or preventing protein translation. The role of exercise as a regulatory stimulus of skeletal muscle miRNAs is now starting to be investigated. This review highlights our current understanding of the regulation of skeletal muscle miRNAs with exercise and disease as well as how they may control skeletal muscle health.
    Frontiers in Physiology 09/2013; 4(266):266. DOI:10.3389/fphys.2013.00266 · 3.50 Impact Factor
  • Source
    • "Indeed, age-associated changes in the cellular environment can be detrimental to satellite cell performance (Conboy et al. 2005; Shefer et al. 2006; Chakkalakal et al. 2012; Barberi et al. 2013). Once isolated from the aging muscle and maintained ex vivo in a rich mitogenic environment or transplanted into a young host environment, satellite cells from old rodents exhibit good regenerative potential (Carlson and Faulkner 1989; Conboy et al. 2005; Shefer et al. 2006; Collins et al. 2007; Carlson et al. 2009). Parabiotic pairing between young and old mice has identified circulating factors in young animals that are capable of improving muscle regeneration in aged tissue (Conboy and Rando 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alpha klotho (known as klotho) is a multifunctional protein that may be linked to age-associated decline in tissue homeostasis. The original klotho hypomorphic (klotho (hm) ) mouse, produced on a mixed C57BL/6 and C3H background, is short lived and exhibits extensive aging-like deterioration of several body systems. Differently, klotho (hm) mice on a pure C57BL/6 background do not appear sickly nor die young, which has permitted us to gain insight into the effect of klotho deficiency in adult life. First, analyzing klotho transcript levels in the kidney, the main site of klotho production, we demonstrated a 71-fold decline in klotho (hm) females compared to wildtype females versus only a 4-fold decline in mutant males. We then examined the effect of klotho deficiency on muscle-related attributes in adult mice, focusing on 7-11 month old females. Body weight and forelimb grip strength were significantly reduced in klotho (hm) mice compared to wildtype and klotho overexpressing mice. The female mice were also subjected to voluntary wheel running for a period of 6 days. Running endurance was markedly reduced in klotho (hm) mice, which exhibited a sporadic running pattern that may be characteristic of repeated bouts of exhaustions. When actually running, klotho (hm) females ran at the same speed as wildtype and klotho overexpressing mice, but spent about 65 % less time running compared to the other two groups. Our novel results suggest an important link between klotho deficiency and muscle performance. This study provides a foundation for further research on klotho involvement as a potential inhibitor of age-associated muscle deterioration.
    Biogerontology 09/2013; 14(6). DOI:10.1007/s10522-013-9447-2 · 3.01 Impact Factor
  • Source
    • "In modern times, the rate of gene–culture coevolution is poised to accelerate even more dramatically as humans begin to direct their own biological evolution through ever-increasing means of horizontal cultural transmission (Brosius, 2003; Hawks et al., 2007; Laland et al., 2010). One cultural source of this change is modern genetic engineering, which in this century may, for those who can afford it, lengthen life spans potentially by decades, eliminate genetic diseases screened before birth, and enhance human strength (Carlson et al., 2009) and possibly intelligence (Sisodiya et al., 2007; Bostrom and Sandberg, 2009; Cheng and Lu, 2012). Many rapid changes that humans face now, and undoubtedly will in the future, are rooted in much slower changes that took place in the past. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Human culture has evolved through a series of major tipping points in information storage and communication. The first was the appearance of language, which enabled communication between brains and allowed humans to specialize in what they do and to participate in complex mating games. The second was information storage outside the brain, most obviously expressed in the "Upper Paleolithic Revolution" - the sudden proliferation of cave art, personal adornment, and ritual in Europe some 35,000-45,000 years ago. More recently, this storage has taken the form of writing, mass media, and now the Internet, which is arguably overwhelming humans' ability to discern relevant information. The third tipping point was the appearance of technology capable of accumulating and manipulating vast amounts of information outside humans, thus removing them as bottlenecks to a seemingly self-perpetuating process of knowledge explosion. Important components of any discussion of cultural evolutionary tipping points are tempo and mode, given that the rate of change, as well as the kind of change, in information storage and transmission has not been constant over the previous million years.
    Frontiers in Psychology 12/2012; 3:569. DOI:10.3389/fpsyg.2012.00569 · 2.80 Impact Factor
Show more