Nutrition, Nitrogen Requirements, Exercise and Chemotherapy-Induced Toxicity in Cancer Patients. A puzzle of Contrasting Truths?

Amino acids can modulate cell metabolism and control cell fate by regulating cell survival and cell death. The molecular mechanisms involved are mediated by the mTOR complexes mTORC1 and mTORC2 activity. These complexes are finely regulated and the continuous advancement of the knowledge on their composition and function is revealing that their balance may represent the condition that determines the cell fate. This is important for normal healthy cells but it is becoming clear, and it is even more important, that the balance of the mTORCs activity may also condition the cell fate of cancer cells. Here, we discuss the evidences supporting the amino acids supplementation as a cancer fighting weapon and a possible strategy to counteract the myocyte toxicity associated with chemotherapy, possibly by tipping the balance of mTORCs activity

Diet, Muscle Protein Synthesis and Autophagy Relationships in Cancer. An Attempt to Understand Where Are We Going, and Why

Protein-based structures are indispensable to maintain life, so identification and removal of worn out structures achieved through proteostasis, the sum of micro and macro-autophagy (autophagy) plus ubiquitin-proteasome system, must balance renewal by new synthesis. Many of the elements controlling dynamically equilibria between protein synthesis and protein degradation have been identified and modalities of activation actively studied, still we are quite far from mastering how this balance is ruled. Failure to maintain a positive balance between protein synthesis and protein degradation would result in sarcopenia, defined as the loss of skeletal muscle mass and function, a major clinical problem frequently accompanying chronic illnesses, but peculiarly spotted in cancer and in elderly patients. Also, how cancer is fed, and how nutrition in cancer patients may affect evolution and therapy effectiveness is another field of opinions and uncertainty. On the other hand, exercise and nutrition tailored to provide adequate amounts of amino acids are widely considered a necessary strategy for prevention and treatment of protein synthetic deficits in muscles. This paper will synthetically review how different nutritional strategies and energy production may interconnect efficiently synthesis and scavenging of aged and overused protein molecules by autophagy. Finally, since energy availability rules life and death of cells and organisms, an hypothesis predicting how energy may control the ratios among protein synthesis and autophagy is proposed: in normal conditions, protein syntheses have a key role in autophagy activation by consuming large amounts of energy when forming peptidic bonds, that is adenosine tri-phosphate (ATP) is consumed to monophospahate (AMP), thus decreasing ATP to AMP ratios. Conversely, both protein syntheses and autophagy may be scarcely activated when low availability of ATP would result also in lowest concentrations of AMP. In this peculiar setting, reduced rates of both protein syntheses and autophagy would be observed, resulting in worsening of protein balance and functions

NOURISHING WOUNDS WITH ESSENTIAL AMINO ACIDS ACCELERATES HEALING IN MIDDLE-AGED RATS

The principal therapy for cutaneous wounds is presently based on protecting the dermis from environmental assault, while simultaneously maintaining a humid environment. In order to improve wound healing, we explored the possibility of using a protective gel that also provides nutrients for wound repair cells. Providing essential amino acids from outside the wound is an unusual and yet potentially efficient support for the healing process. In skin wound repair of middle-aged rats, we found that nourishing wounds with essential amino acids shortened repair time, by reducing inflammation and influencing a full set of regulators of collagen-1 deposition and removal, such as transforming growth factor beta, its receptors and matrix metalloproteinases. Nourishing wounds with essential amino acids optimizes the quality and organization of collagen-1 deposition, thus accelerating the wound healing process compared with placebo. Topical application of essential amino acids appears to be a promising strategy in reducing healing time and potentially improving the quality of repairs

Nutrition and skin healing, the role of nitrogen intake. Is “from in” predominant on “from out” ?

Skin is an organ, and not merely a tissue, which accounts for 8% of body total weight. Protein content, predominantly collagen, in turn accounts for 50% of skin weight. Therefore, protein contained into skin are in balance with protein metabolism of the whole body, and skin synthesizes new proteins or is dismantled for providing nitrogen containing substrates according the needs of body metabolism. We have observed that diets containing poor amino acidic quality, that is poor in essential amino acids content, compromise rapidly collagen density and affects collagen synthesis unbalancing collagen metabolism towards protein catabolism and impaired syntheses. Thus, we suggest to monitor plasma albumin levels as simple and widely available method for screening patients both at increased risk of spontaneous lesions, like bed sores, and/or failure of topical therapy and impaired wound healing due to under-evaluating the impact of protein malnutrition in patients. La cute è un organo, e non solamente un tessuto, che costituisce l’8% del peso corporeo di un adulto sano. Il contenuto proteico della cute, in cui predomina il collagene, a sua volta costituisce il 50% del peso di questo tessuto. Pertanto, è comprensibile che le proteine contenute nella cute siano in rapporto con lo stato metabolico del corpo, e quindi che la cute sintetizzi nuove proteine o le catabolizzi per provvedere il rifornimento di substrati azotati al metabolismo secondo le esigenze e le necessità del resto del corpo. Noi abbiamo dimostrato che diete a bassa qualità di contenuto in amino acidi , cioè povere in amino acidi essenziali, rapidamente compromettono la densità del collagene e sbilanciano il rapporto fra sintesi e catabolismo , inducendo una alterazione negative della sintesi del collagene cutaneo. Perciò, suggeriamo che controllare con regolarità almeno i livelli di albumina plasmatica, un marcatore generale di sintesi proteica adeguata, sia un semplice e facilmente disponibile metodo sia per identificare i pazienti a maggior rischio di lesioni spontanee, come le piaghe da decubito, sia per comprendere se il fallimento della terapia topica nella riparazione di qualunque lesione sia da ascriversi alla malnutrizione del paziente e non alla inadeguatezza della medicazione locale

Influence of diets with varying essential/nonessential amino acid ratios on mouse lifespan

An adequate intake of essential (EAA) and non-essential amino acids (NEAA) is crucial to preserve cell integrity and whole-body metabolism. EAA introduced with diet may be insufficient to meet the organismal needs, especially under increased physiological requirements or in pathological conditions, and may condition lifespan. We therefore examined the effects of iso-caloric and providing the same nitrogenous content diets, any diet containing different stoichiometric blends of EAA/NEAA, on mouse lifespan. Three groups of just-weaned male Balb/C mice were fed exclusively with special diets with varying EAA/NEAA ratios, ranging from 100%/0% to 0%/100%. Three additional groups of mice were fed with different diets, two based on casein as alimentary proteins, one providing the said protein, one reproducing the amino acidic composition of casein, and the third one, the control group, was fed by a standard laboratory diet. Mouse lifespan was inversely correlated with the percentage of NEAA introduced with each diet. Either limiting EAA, or exceeding NEAA, induced rapid and permanent structural modifications on muscle and adipose tissue, independently of caloric intake. These changes significantly affected food and water intake, body weight, and lifespan. Dietary intake of varying EAA/NEAA ratios induced changes in several organs and profoundly influenced murine lifespan. The balanced content of EAA provided by dietary proteins should be considered as the preferable means for “optimal” nutrition and the elevated or unbalanced intake of NEAA provided by food proteins may negatively affect the health and lifespan of mice

Effects of voluntary wheel running and amino acid supplementation on skeletal muscle of mice

The aims of the present study were as follows: (1) to examine the adaptational changes to chronic endurance voluntary exercise and (2) to investigate the effects of amino acid supplementation on the adaptational changes induced by endurance training in hindlimb (gastrocnemius, tibialis, soleus) and respiratory (diaphragm) muscles of mice. Male C57Bl6 mice were divided in four groups: control sedentary, sedentary supplemented with amino acid mixture (BigOne, 1.5 mg g day(-1) in drinking water for 8 weeks), running (free access to running wheels for 8 weeks), and running supplemented with amino acid mixture. Myosin heavy chain (MHC) isoform distribution was determined in all muscles considered. Fiber cross-sectional area (CSA) was measured in the soleus muscle. In all muscles except the tibialis, endurance training was associated with an overall shift towards the expression of slower MHC isoforms. Amino acid supplementation produced a shift towards the expression of faster MHC isoforms in the soleus and diaphragm muscles, and partially antagonized the effects of training. Immunohistochemical analysis of CSA of individual muscle fibers from the soleus muscle suggests that voluntary running produced a decrease in the size of type 1 fibers, and amino acid supplementation during training resulted in an increase in size in both type 1 and type 2A fibers. Collectively, these results suggest that the endurance adaptations induced by voluntary running depend on the muscle type, and that amino acid supplementation is able to modulate both fiber size and MHC isoform composition of skeletal muscles in sedentary and exercised mice