MK-677 Increases Lean Muscle Mass in Elderly

elderly manIt has been estimated that most people lose between 35% and 45% of skeletal muscle in the 6 decades between the ages of 20 and 80. This progressive loss of muscle is known as sarcopenia and, combined with osteoporosis, is responsible for the loss of strength, increasing frailty, and loss of independence seen in many elderly people.

Along with lack of regular exercise, declining levels of growth hormone are thought to be linked to muscle loss. A new study published in Annals of Internal Medicine describes the effect of the orally active ghrelin agonist, MK-677, in healthy adults aged 60-81 years.


Daily dosing with 25mg MK-677 was generally well tolerated and increased levels of growth hormone and insulin-like growth factor-1 to those of healthy young adults. Over 1 year, mean fat-free mass declined in the placebo group, but increased by 20% in the MK-677 treated group. MK-677 induced a transient increase in appetite; body weight increased by 2.7 kg in the MK-677 treated group, but by only 0.8 kg in the placebo treated group. Overall, treatment with MK-677 had a positive effect on three factors that contribute to loss of muscle mass: reduced growth hormone levels, loss of fat-free mass, and inadequate food intake. The increase in lean mass seen with MK-677 therapy did not translate into enhanced strength or function, but the researchers say that “the study sets the stage for an adequately powered clinical trial of sufficient duration in a population vulnerable to frailty”.

New Target in Fight Against Obesity

A recent report in the journal Cell Metabolism (Cell Metab. 2008,7(5):377-388) identifies the serine/threonine kinase, calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2), as a key component of the ghrelin signalling pathway. Ghrelin, which is produced in the stomach, is a polypeptide that promotes food intake by increasing production of the appetite-stimulating neurotransmitter, neuropeptide Y, by the hypothalamus. The authors established the role of CAMKK2 in appetite control and glucose tolerance both by experiments with CAMKK2-null mice and by administering the CAMKK2 inhibitor, STO-609, to normal mice. CAMKK2 is expressed at low levels in peripheral tissue and the effects of inhibition are likely to be brain-specific. The results suggest that blocking CAMKK2 has the potential to promote weight loss and improve glucose tolerance.


Other approaches to the management of obesity targeting the ghrelin pathway are being investigated. A group at the Scripps Institute has developed an anti-obesity vaccine that is directed against ghrelin and a number of groups are investigating small molecule modulators of the ghrelin receptor.