Date Published: December , 2010
Publisher: Blackwell Publishing Ltd
Author(s): Aphrodite Vasilaki, Jack H van der Meulen, Lisa Larkin, Dawn C Harrison, Timothy Pearson, Holly Van Remmen, Arlan Richardson, Susan V Brooks, Malcolm J Jackson, Anne McArdle.
In muscle, aging is associated with a failure of adaptive responses to contractile activity, and this is hypothesized to play an important role in age-related loss of muscle mass and function. Mice lacking the Cu,Zn superoxide dismutase (Cu,ZnSOD, SOD1) show an accelerated, age-related loss of muscle mass and function. This work determined whether adult mice lacking Cu,ZnSOD (Sod1−/− mice) show a premature failure of adaptive responses to contractions in a similar manner to old wild-type (WT) mice. Adult Sod1−/− mice (6–8 months of age) had a ∼ 30% reduction in gastrocnemius muscle mass compared with age-matched WT mice. This lower muscle mass was associated with an activation of DNA binding by NFκB and AP-1 at rest. Measurements of the activity of reactive oxygen species (ROS) in single fibres from the muscles of Sod1−/− mice at rest indicated an elevation in activity compared with fibres from WT mice. Following 15 min of isometric contractions, muscle fibres from WT mice showed an increase in the intracellular ROS activities and activation of NFκB and AP-1, but no changes in either ROS activity or NFκB and AP-1 activation were seen in the muscles of Sod1−/− mice following contractions. This pattern of changes mimics that seen in the muscles of old WT mice, suggesting that the attenuated responses to contractile activity seen in old mice result from chronic exposure to increased oxidant activity. Data support the use of the Sod1−/− mouse model to evaluate potential mechanisms that contribute to the loss of muscle mass and function in the elderly.
Age-related loss of muscle mass and strength is the major contributor to frailty and loss of independence in the elderly (Marcell, 2003) such that by the age of 70, the cross-sectional area of skeletal muscle is reduced by 25–30% and muscle strength is reduced by 30–40% (Porter et al., 1995). Increased levels of products of oxidative reactions are associated with the age-related decline in muscle mass and function. Skeletal muscle of aged rodents contains the increased amounts of the products of oxidative damage to biomolecules such as lipid, DNA and proteins in comparison with young or adult rodents (Nohl, 1993; Lass et al., 1998; Schoneich, 1999; Reid & Durham, 2002; Drew et al., 2003; Sastre et al., 2003; Broome et al., 2006; Vasilaki et al., 2007) although definitive evidence for a role of oxidative damage in the development of age-related loss of muscle mass and function is lacking (Pérez et al., 2009).
Western blots of the Cu,ZnSOD (SOD1) protein in gastrocnemius muscles from adult WT and Sod1−/− mice are shown in Fig. 1A together with representative blots for MnSOD (SOD2). Muscles from the Sod1−/− mice had no detectable Cu,ZnSOD protein. In contrast, muscles from the Sod1−/− mice showed a small but statistically significant increase in MnSOD content (Fig. 1B).
Although it is well documented that tissues, such as skeletal muscle, from aging organisms contain increased amounts of the products of oxidative reactions (Nohl, 1993; Lass et al., 1998; Schoneich, 1999; Reid & Durham, 2002; Drew et al., 2003; Sastre et al., 2003; Broome et al., 2006; Vasilaki et al., 2007), whether oxidative damage plays a direct role in fundamental processes of aging remains unclear (Muller et al., 2007b; Pérez et al., 2009). In recent years, it has become widely recognized that ROS are not inevitably damaging. Moreover, ROS exert physiological roles in cell signalling processes, and cells adapt to increases in the generation or activity of ROS by increasing the expression of proteins that protect against oxidative damage (McArdle et al., 2001; Jackson et al., 2002). A key process by which this occurs is through the activation of redox-sensitive transcription factors (Jackson et al., 2002). NFκB and AP1 are involved in the upregulation of antioxidant enzymes such as SOD and catalase in response to oxidative stress (Zhou et al., 2001; Jackson et al., 2002), and HSF1 is important for HSP expression in response to acute stress (Cotto & Morimoto, 1999). In adult mice, activation of NFκB, AP-1 and HSF occurs in skeletal muscle following an isometric contraction protocol that also caused increased ROS generation and resulted in an increased muscle content of HSPs, SOD and catalase (Vasilaki et al., 2006c; Palomero et al., 2008).