DIETARY SUPPLEMENTATION WITH SPECIFIC AMINO ACID MIXTURES PROMOTES MITOCHONDRIAL BIOGENESIS: HYSIOLOGICAL AND PATHOPHYSIOLOGICAL RELEVANCE IN MAMMALS

Nutrients are major regulators of biochemistry and physiology in living organisms, and subtle changes in nutrient composition result in genetic or epigenetic control of processes influencing healthspan and survival. Though contentious Abstracts Ann Nutr Metab 2013;63(suppl 1):1–1960 99 yet, calorie restriction (the reduced intake of calories as foods without malnutrition) postpones several age-related diseases, hence extending healthspan and lifespan in many species. The molecular basis of this long known phenomenon are still elusive, albeit evidence seem to converge on the reduction of mitochondria-derived oxidants through the generation of new, more efficient organelles (mitochondrial biogenesis) (Nisoli et al., Science 310: 314-317, 2005). Branched-chain amino acids (BCAAs) display healthy effects both in animals and humans (Valerio et al., Aging 3: 464-478, 2011). Notably, we reported that unlike other amino acid mixtures, a BCAA-enriched mixture (BCAAem), promoted mitochondrial biogenesis in cultured cardiomyocytes and skeletal myocytes as well as in heart and skeletal muscles of sedentary and trained middle-aged mice. This was accompanied by muscle fiber rejuvenation, improved locomotor activity and coordination, and extension of average lifespan (D´Antona et al., Cell Metab 12: 362-372, 2010), suggesting that BCAAem acts as a CR mimetic. We then investigated the BCAAem effects on statin-induced muscle damage in mice. Though known to be rather safe, statin use is associated with an elevated risk of myopathy, ranging in severity from asymptomatic increases in creatine kinase to muscle weakness, aches and fatigue, up to the rare fatal rhabdomyolysis. We found that BCAAem prevented atorvastatin- and rosuvastatin-induced structural and functional deterioration of skeletal muscles in both wild-type and hypercolesterolemic mice (ApoE receptor knockout mice on a high-fat diet). Statin prescription is expected to grow alongside the aging of population. Dietary supplementation with specific amino acid mixtures may be an effective strategy to avoid common adverse effects limiting the adherence to statin therapy in human subjects.