During ageing, there is a progressive onset of insulin resistance (Pagano et al., 1981), shown by aberrant regulation of glucose and protein metabolism. However, insulin resistance is not routinely treated unless diabetes develops. Data suggests that insulin resistance precedes sarcopenia, and may therefore play a fundamental role in its development (Rasmussen et al., 2006). There is mounting evidence in support of this hypothesis that sarcopenia may be a result of age-related insulin resistance (Fujita et al., 2007).

The molecular pathways that underlie the age-related development of insulin resistance in skeletal muscle are complex and incompletely understood. IR is associated with mitochondrial dysfunction that has been proposed to lead to accumulation of intramyocellular lipid and defective insulin signalling (Petersen et al., 2003).  Ageing is also associated with an increase in reactive oxygen species generation (ROS) and evidence suggests that this increase in ROS generation with ageing may lead to insulin resistance.  This suggestion that ROS and insulin resitance are intrinsically linked is supported by data showing that mice with a homozygous knockout for neuronal nitric oxide synthase (nNOS) have increased oxidative stress in muscle and also exhibit severe insulin resistance. Further data linking ROS generation and IR comes from studies of the anti-diabetic drug, Metformin that corrects IR. This compound has recently also been shown to stimulate AMP-activated kinases and enhance nitric oxide (NO) synthesis, which may reduce superoxide bioavailability and thus reduce oxidative stress. Once IR is established in muscle of old people and animals, this may potentially lead to a vicious cycle of increased blood glucose levels resulting in further oxidative stress, further ineffective increases in circulating insulin concentration and catabolic effects on the muscle (Leverve, 2003).

In ‘insulin sensitive' skeletal muscle the binding of insulin to its receptor activates 2 major signalling pathways; these pathways are the Ras-Raf-MEK-ERK pathway and the PI3K/AKT pathway. The first pathway does not appear to be involved in modifications to muscle fibre size (but is involved in fibre type composition) whilst the second pathway has major effects on muscle fibre hypertrophy and protein degradation (see Figure 1). Insulin stimulated phosphorylation of AKT increases protein synthesis via GSK and mTOR kinases. Furthermore, phosphorylation of AKT results in the downstream phosphorylation of the Forkhead box O (Foxo) class of transcription factors. In its phosphorylated state, FOXO remains in the cytosol, however dephosphorylated FOXO is capable of nuclear translocation where it triggers protein degradation through atrogenes such as MuRF1 and MAFbx (Sandri et al, 2004). Therefore we propose that ageing results in increased generation of ROS which results in the development of insulin resistance with impaired insulin signalling and consequently increased muscle protein degradation and decreased protein synthesis, resulting in sarcopenia. 

Figure 1. Schematic representation of the insulin signalling cascade demonstrating the effects of insulin on protein synthesis and degradation.

Dr Close is supported by a Fellowship award from Research into Ageing.