Omega-3 fatty acids for the treatment of the anabolic resistance of skeletal muscle in older adults

Bettina Mittendorfer, Ph.D.

Project Overview:
Loss of muscle mass is a normal consequence of aging, worsened by chronic illness, poor appetite and diet, and reduced physical activity.  The ensuing decline in strength, endurance, balance, and mobility are a major cause of frailty and disability, which often lead to admission to assisted living facilities and premature death.  A major cause for loss of muscle mass in advanced age is the inability of aging muscle to adequately increase muscle protein synthesis (MPS) in response to nutritional stimuli (e.g., amino acids and insulin).  The inability to stimulate MPS is likely mediated by insulin resistance and low-grade inflammation, which interfere with the intracellular anabolic signaling cascade.  We therefore hypothesize that therapeutic interventions that have anti-inflammatory properties and can overcome this anabolic signaling resistance increase MPS in the elderly and slow the loss of muscle mass.  Long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFA) activate the intracellular insulin signaling cascade in muscle and have anti-inflammatory properties.  However, the effect of LCn-3PUFA on human muscle protein metabolism is not known and data from studies in animal models are scarce and controversial.  Our aim is to evaluate the effect of LCn-3PUFA on: i) protein synthesis, ii) anabolic signaling pathways, and iii) inflammatory signaling pathways in skeletal muscle of older adults.  We hypothesize that LCn-3PUFA decrease the plasma concentration of pro-inflammatory cytokines, decrease the activity of inflammatory pathways in skeletal muscle, increase the activation of anabolic signaling pathways in muscle by hyperinsulinemia-hyperaminoacidemia, and increase the stimulatory effect of hyperinsulinemia-hyperaminoacidemia on MPS.  To test these hypotheses, we will measure the rate of skeletal MPS (by using stable isotope labeled tracer techniques) and the content and phosphorylation of components of anabolic and inflammatory signaling pathways during basal, postabsorptive conditions and during hyperinsulinemia-hyperaminoacidemia in older adults before and after treatment with either LCn-3PUFA or placebo.  If the results from our studies confirm our hypotheses, LCn-3PUFA could provide a safe, simple, and low cost intervention to deter the onset of sarcopenia (i.e., the age-associated loss of muscle mass).  Future studies will be designed to: i) investigate the effect of LCn-3PUFA on muscle mass and function, physical performance and quality of life in a randomized, placebo-controlled trial, ii) further evaluate the mechanisms responsible for the beneficial effect of LCn-3PUFA on muscle protein metabolism, and iii) evaluate whether the red blood cell membrane and/or muscle phospholipid fatty acid composition can be used as biomarkers for the age-associated loss of muscle mass and thus the risk of frailty and premature death.

Final Report Abstract:
Loss of muscle mass is a normal consequence of aging, worsened by chronic illness, poor appetite and diet, and reduced physical activity in many older adults. The ensuing decline in physical function is a major cause of frailty, disability and death. Approximately half of the population over 60 y of age is considered sarcopenic (i.e., muscle mass one standard deviation or more below the sex-specific value for young adults). Treatments that can reverse or reduce the age-associated loss of muscle mass are therefore much needed. Anabolic resistance, i.e., the inability of aging muscle to adequately increase muscle protein synthesis and decrease muscle breakdown in response to nutritional anabolic stimuli (e.g., amino acids and insulin) is considered a major cause for the loss of muscle mass in advanced age.

Evidence is emerging that long-chain omega-3 polyunsaturated fatty acid (LCn-3PUFA) consumption may be important for maintenance of muscle mass and physical function throughout the life-span. For example, feeding fish oil, which is rich in LCn-3PUFA, was found to increase whole-body disposal of amino acids in growing steers. And, fatty fish consumption was found to be the most important independent dietary factor in relation to grip strength in the Hertfordshire, UK study, including 2983 men and women aged 59 to 73 y. These findings have led us to hypothesize that dietary LCn-3PUFA supplementation stimulates muscle protein anabolism. To test this hypothesis, we measured the protein fractional synthetic rate (FSR) and the phosphorylation of elements of the anabolic pathway (Akt, mTOR, and p70s6k) during basal, postabsorptive conditions and during a hyperinsulinemic-hyperaminoacidemic clamp and muscle protein, RNA, and DNA concentrations before and after eight weeks of LCn-3PUFA supplementation (4 g·d-1 of Lovaza™) in two groups of older adults who were randomized to receive LCn-3PUFA or an isoenergetic LCn-3PUFA free control-oil for 8 weeks. Our preliminary results indicate that dietary LCn-3PUFA supplementation stimulates protein anabolism in human muscle and might therefore be useful for the prevention and treatment of sarcopenia. Read the full Final Report.