Lipogenic regulators are elevated with age and chronic overload in rat skeletal muscle

The loss of muscle mass and function with age, or sarcopenia, is associated with substantial social and economic costs as a result of impairments in strength and function, which ultimately lead to physical disability and institutionalization (Frontera et al. 1991, Baumgartner et al. 1998). Despite these observations, the idea that a decline in physical functioning is fundamentally related to a decrease in muscle mass remains controversial. Both muscle mass and strength decline with age, but the loss of strength far surpasses what is projected based on the decline in mass (Hughes et al. 2001, Lauretani et al. 2003, Goodpaster et al. 2006, Stenholm et al. 2008). This may be explained by deterioration in muscle quality including decreased fibre size and number, reduced contractility of fibres, motor neurone loss and intramyocellular lipid infiltration (Lexell et al. 1988, Sipila & Suominen 1994, Larsson et al. 1997, Visser et al. 2000, Goodpaster et al. 2001, Delbono 2003, Cree et al. 2004). Interestingly, in several epidemiological studies the accumulation of fat mass has been shown to be a strong independent predictor of subsequent functional loss and disability (Sipila & Suominen 1994, Visser et al. 2000, Goodpaster et al. 2001). The master transcription factor, sterol regulatory element-binding protein (SREBP) 1, mediates transcriptional effects on lipogenic genes including fatty-acid synthase (FAS), acetyl-CoA carboxylase (ACC) and stearoyl-CoA desaturase (SCD) (Osborne 2000, Dobrzyn & Dobrzyn 2006, Sampath et al. 2007, Wang et al. 2009). These enzymes catalyse the synthesis of fatty acids that are the key substrates for the formation of complex lipids such as triglycerides, diglycerides and ceramides, which have been shown to be upregulated in obesity and insulin resistance (Hyde et al. 2005, Summers & Nelson 2005, Brownsey et al. 2006, Dobrzyn & Dobrzyn 2006, Holland et al. 2007, Lessard et al. 2007, Sampath et al. 2007, Erion & Shulman 2010). However, their function in age-associated skeletal muscle loss and anabolic resistance are currently unknown. The 5′AMP-activated protein kinase (AMPK) is a sensor of cellular energy homeostasis and has well-established roles in the regulation of glucose and lipid metabolism (Hawley & Lessard 2008, Osler & Zierath 2008, Witczak et al. 2008, Steinberg & Kemp 2009). Recently, it has been recognized that AMPK activation is increased in both aged skeletal muscle (Thomson & Gordon 2005, Thomson et al. 2008, 2009) and in the presence of increased lipids or a high-fat diet (Watt et al. 2006, Lessard et al. 2007) and may have a function in the inhibition of the response of aged skeletal muscle to contraction-induced anabolic stimulation (Thomson et al. 2009). In support of this contention, the AMPKα1 catalytic subunit is thought to have a role in the prevention of excess muscle growth by the inhibition of the mammalian target of rapamycin (mTOR) anabolic pathway (Mounier et al. 2009, McGee et al. 2008, Rivas et al. 2009a). We (Parkington et al. 2004, Funai et al. 2006, Chale-Rush et al. 2009) and others (Cutlip et al. 2006, Thomson & Gordon 2006, Baker et al. 2008, Dennis et al. 2008, Drummond et al. 2008, Kumar et al. 2009) have previously demonstrated that the ability of aged humans (Dennis et al. 2008, Drummond et al. 2008, Kumar et al. 2009) and rodents (Parkington et al. 2004, Thomson & Gordon 2005, 2006, Cutlip et al. 2006, Funai et al. 2006, Baker et al. 2008, Chale-Rush et al. 2009) to adapt (i.e. hypertrophy, increased anabolic signalling, etc.) following overload is blunted compared with young. Therefore, the aim of the present study was to determine what role age-related lipid accumulation in skeletal muscle has on muscle growth in response to 28 days of muscle overload. For this purpose, we determined the storage of triglycerides in skeletal muscle, the concentration of SREBP1 and its transcriptional target genes, the activation of AMPK and the concentration of the isoforms of AMPKα. We hypothesized that the storage of lipids would be increased in aged skeletal muscle and this would be associated with an increase in lipogenic capacity leading to the activation of AMPK even in animals that have undergone chronic skeletal muscle overload.