for some time, until all amp is eliminated from the muscle cell. the muscle movements become noticeably less precise. breathing slows down, and from this moment reacts very weakly to the load and not at all to the perceived effort. it becomes hard to rapidly increase the load on a muscle, as in mcardle's disease, and such a rapid load increase will dump even more purines into blood and urine (looking like translucent or rust-colored sharp shiny crystals and being highly irritating). the same situation would occur if blood flow to muscle cells becomes insufficient (except that somewhat less amp is spilled over, and somewhat more of it is metabolized inside the muscle cell). on the other hand, there will be no lasting muscle pain from lactate, and continuous aerobic activity is possible. oxidation of odd-numbered saturated fatty acids may provide another mechanism, although very gradual, to up-regulate citric acid cycle during exercise. as the short-term regulation of atp production becomes very weak after the exhaustion of glycogen, the medium-term regulation becomes enabled, but with a progressively weaker authority at higher purine nucleotide energy charge levels, which causes some differences in symptoms compared to mcardle's. in mcardle's, the highly active amp deaminase, which additionally experiences amplification from the bloated amp pool due to the lack of the moderating effect of myophosphorylase, is able to produce a readily observable "second wind" phenomenon almost exactly 7 minutes after a significant load increment. in ampd deficiency, glycogen-less muscles will feel mostly the same by the time they become able to take another load increment. a load decrement may produce some sense of relief, though, if the pool of the citric acid cycle intermediates built up so far is sufficient to maintain full purine nucleotide energy charge at the lower load. it is unclear, what, if anything, does it take to unknowingly trigger rhabdomyolysis at this point, assuming the muscle cell is otherwise healthy. adenosine production and lack of ammonia overproduction seem to strongly suppress rhabdomyolysis down to the purine nucleotide energy charge level, where the cell is able to signal pain, or where individual muscle fibers start cramping (fail to relax from contraction in sync with the rest of the muscle), or the whole muscle fails to contract (when walking quickly downhill), allowing the person to appropriately modulate the exertion. most of the amp probably spills into blood unchanged, and is gradually returned to the muscle cell, if its concentration there falls due to gradual recharge to atp. the blood thus plays a role of a big amp buffer. idle muscles may also take up some free amp. the spillover also limits, how much the residual ampd activity can be amplified in this state. thus, it may take the residual ampd activity less time to build up citric acid cycle intermediates, when the whole body is warmed up for an exercise at the same time, rather than a specific group of muscles needed in the exercise. in case of leg muscles, where circulation is substantially dependent on their cyclical contraction when the body is upright, a small but useful degree of initial up-regulation of the citric acid cycle may be achieved just by standing still for a few minutes. it is most useful when a long period of rest, or sitting in a vehicle, must be followed by brisk walking. if the person keeps standing still for longer, rather than restoring circulation in the leg muscles (e.g. by sitting down, walking, or cycling), the ammonia, produced by the amplified residual ampd activity, may accumulate in the muscle cells and in the surrounding tissues to toxic levels, and may also indirectly affect other organs. there is little or no warning for nearing toxicity, because the purine nucleotide energy charge is still relatively high, the leg muscles do not cramp, and remain functional. in contrast, while muscle glycogen is available, accumulation of lactic acid in this situation would produce a noticeable sensation. on the other hand, in persons with balanced ampd and myophosphorylase activities in muscle cells, lactic acid and ammonia are produced simultaneously, counteracting each other's effects to some degree. some seldom used but strong voluntary muscles, such as those involved in "pushing" during the act of defecation, are not tuned for aerobic mode, and may dump plenty of purines during their short work routine, if it happens in this state. if a food containing even small but perceivable amount of sugar (simple sugars or disaccharides that can be tasted sweet, or starch that is at least minimally hydrolyzed by salivary amylase, or even some non-sugar sweeteners) is eaten in this state, there may be a period of time after it enters stomach and before bulk absorption occurs, when continuous exercise becomes very hard, and easily triggers rhabdomyolysis. it probably happens because the digestive system senses and signals forthcoming delivery of sugars, inhibiting fatty acid release and oxidation, and starving glycogen-less muscle cells of the sole available source of energy. even simple continuous exercise, like walking or washing dishes by hand right after the meal, may trigger rhabdomyolysis in the exercising muscles. this rhabdomyolysis is probably not of exertional, but of hypoglycemic nature, as loaded glycogen-less muscles can rapidly remove glucose from blood, and the normal mechanism of glucose homeostasis lacks the required responsiveness or capacity to prevent hypoglycemia. the broken down myocytes probably do not yield much glucose. unlike the case with exertional rhabdomyolysis, there is no warning. at rest, however, the liver will effortlessly cover the whole body energy needs until absorption of carbohydrates occurs. if a large group of muscles is still actively drawing fuels from blood after the most recent continuous exercise, in order to replenish the atp and the phosphocreatine reserve, it may become sour without any additional exercise by the time the carbohydrate meal is finished. if the carbohydrate meal consists of a food (which doesn't need to be carbohydrate itself), that requires prolonged vigorous chewing, and then some time to be digested, for instance parboiled long grain rice, chewing may suddenly become very slow and difficult halfway through the meal. when a carbohydrate-rich food has been eaten before amp has been eliminated from muscle cells, when bulk absorption starts, plenty of glucose becomes available in the blood, is taken up by muscle cells, is added to the glycogen store, but then immediately becomes liberated by the still up-regulated myophosphorylase. the resulting excess of glucose is metabolized down to lactic acid (the body cannot increase aerobic metabolism in an instant), recharging all amp to atp. the lactate is dumped back into blood and urine. the higher the glycemic index of the food is, the greater proportion of carbohydrates (and calories) is wasted into urine. if the person is at rest at this moment, and pays attention, a sudden increase in the breathing frequency due to lactate dumping is readily observable. if the rise in the blood lactate is particularly sharp, and the person happened to be breathing slowly, a heart palpitation may sometimes be observable. the lactic acidosis with palpitation may also occur during sleep, if stomach emptying has been delayed e.g. due to digestion requirements of the food or its high volume, and the person went to sleep before absorption has started. in this case the person will be awaken in a state of distress, with rapid breathing. the person may recall seeing a nightmare. delayed stomach emptying creates especially favorable conditions for the shock lactic acidosis, because the digestive system may meanwhile still inhibit fatty acid release and oxidation, helping more muscles to run out of glycogen in those persons, who are otherwise still able to maintain its stores between meals. it has been experimentally demonstrated, that delayed gastric emptying prolongs the duration of the glp-1 signal. notably, a small quantity of dietary fructose does not produce this effect (the lactic acidosis), as it is captured by liver and may be fully expended for replenishing liver glycogen. once all amp has been recharged to atp, and glycogen stores allowed to replenish, the cell transitions back to the unmodified original state. if carbohydrate-rich food is not consumed in this state, amp elimination from the cell eventually completes, glycogen stores can be replenished again, and the cell transitions back to the original state but with reduced atp pool and an up-regulated citric acid cycle. it may be especially important to have adequate dietary iodine in the glycogen-less state, so that stomach emptying is not excessively delayed, the up-regulation of the citric acid cycle in muscle cells in response to a load increment is not too slow, and the muscles can each time accept a bigger load increment relative to the perceived effort. diagnosis the diagnosis of madd needs to be considered in patients who have exercise induced myalgia, cramps and sometimes weakness. a mildly elevated creatine kinase may also occur. exclusion of other muscular diseases such as mcardle's disease and carnitine cycle abnormalities should occur. madd may be identified if there is a lack of ammonia rise after forearm exercise testing. the diagnosis may then be confirmed with genetic testing. treatment it is important for madd patients to maintain strength and fitness without exercising or working to exhaustion. learning this balance may be more difficult than normally, as muscle pain and fatigue may be perceived differently from normal individuals. symptomatic relief from the effects of madd may sometimes be achieved by administering ribose orally at a dose of approximately 10 grams per 100 pounds (0.2 g/kg) of body weight per day, and exercise modulation as appropriate. taken hourly, ribose provides a direct but limited source of energy for the cells. patients with myoadenylate deaminase deficiency do not retain ribose during heavy exercise, so supplementation may be required to rebuild levels of atp. creatine monohydrate could also be helpful for ampd patients, as it provides an alternative source of energy for anaerobic muscle tissue and was found to be helpful in the treatment of other, unrelated muscular myopathies.