Year

2010

Degree Name

Doctor of Philosophy

Department

School of Health Sciences

Abstract

Background: Dietary fish oil is associated with many health benefits. Changes in membrane composition in the heart with incorporation of n-3 polyunsaturated fatty acids (n-3 PUFA), especially docosahexaenoic acid (22:6n-3, DHA) have been associated with improved function and reduced cardiac disease morbidity and mortality. Although similar incorporation of DHA is observed in skeletal muscle, very little is known about the effects of fish oil on skeletal muscle function. Preliminary work suggests an important role for fish oil in improving muscle function in rats. If dietary fish oil can affect skeletal muscle similarly to the heart, the potential applications are huge, including improving muscle function and quality of life in those with a sedentary lifestyle, athletes and sportspeople as well as patients with secondary skeletal muscle dysfunction, for example in heart failure and respiratory disorders. A general concern however with previous animal mechanistic studies (both in the heart and skeletal muscle) that show an effect of fish oil, use high doses of dietary fish oil that are generally not comparable to human intakes. The purpose of this PhD was to therefore assess the effects of low, human equivalent doses of dietary fish oil on skeletal muscle membrane composition, function and fatigue. Muscle function and fatigue was assessed in normal physiological conditions, in muscle already fatigued by prior activity (post-fatigue) and in muscle subjected to restricted blood flow (model of claudication). In addition, we set out to extend this study to apply it to a model of heart failure.

Methods/Design: 144 Male Sprague-Dawley rats were assigned to one of three pre-fabricated diets. Rats were fed 10% fat diets containing either fish oil (FO) in olive oil (LowFO-0.31% or ModFO-1.25%) or olive oil diet alone (OO) for at least 4 weeks prior to experimentation. Skeletal muscle function was assessed in vivo using the constant flow auto-perfused hindlimb set up with different stimulation protocols including single tetanic contractions, continuous low frequency (2Hz) twitch stimulation and repeated bouts of low frequency (5Hz) stimulation. The repeated bouts stimulation protocol (5Hz) was used to assess function in muscle post-fatigue and in the claudication model, as it is more representative of human muscle activity. Abdominal aortic banding was chosen as the most relevant model of cardiac hypertrophy and heart failure for the current study. As it has not previously been used for assessment of the skeletal muscle dysfunction associated with heart failure, preliminary work sought to identify this model as one that causes significant skeletal muscle dysfunction. In addition, the effect of FO on the development of cardiac hypertrophy was examined by measuring heart size. Echocardiography was later introduced as a tool to improve the assessment of heart function in the aortic banding model.

Outcomes: Both low and moderate dose FO diets resulted in significant changes in membrane composition, including a marked increase in DHA incorporation in gastrocnemius (OO: 9.26±0.74%; LowFO: 19.89±0.36%; Mod FO: 24.25±1.03%) and soleus muscle (OO: 5.14±0.23%; LowFO 14.27±0.65%; ModFO: 18.04±1.40%) comparable to the myocardium (OO: 6.62±0.34%; LowFO: 16.84±0.38%; ModFO: 20.35±0.68%). Skeletal muscle force development was higher in FO fed animals during tetanic contractions and repetitive single twitch contractions. The FO fed animals were resistant to fatigue during repetitive single twitch contractions and during repeated trains of contraction with a higher force maintained throughout each 5min stimulation protocol, both in normal and postfatigue muscle. This effect was less obvious in a model of low flow. Associated with these improvements in muscle contractile function were improvements in O2 consumption in FO animals. Low dose FO prevented cardiac hypertrophy after aortic banding when introduced prior to surgery and produced a small reduction in hypertrophy when the FO diet was introduced after the hypertrophic stimulus in comparison to OO controls. The abdominal aortic banding model of heart failure did not result in any observed differences in skeletal muscle function in the time frame investigated. Echocardiography indicated reduced HR and increased stroke volume in FO fed animals not subjected to aortic banding.

Conclusion: This study established that dietary FO improved skeletal muscle force development and promoted fatigue resistance that was universally applicable over a range of contraction patterns. This was achieved with very low FO doses equivalent to human intakes (in energy terms), which nevertheless produced marked increases in muscle DHA incorporation. These low fish oil doses were also sufficient to slow resting heart rate and improve cardiac function in vivo. Heightened O2 consumption likely contributes to the improved muscle performance. Low dose fish oil was also beneficial in reducing the development of cardiac hypertrophy, however no skeletal muscle dysfunction was observed at the time point examined in this model, preventing the assessment of the potential for fish oil to improve muscle function associated with heart failure. These studies confirm and extend previous findings pertaining to the effect of n-3 PUFA on heart and skeletal muscle function achieved previously using high fish oil intakes. The use of fish oil doses achievable in the human diet confirms a relevance to human physiology that was previously questionable.

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