You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
the most crucial task of the mitochondrion is the generation of energy as adenosine triphosphate , by means of the electron transport chain .
they are one of the commonest inherited neuromuscular diseases , with an estimated prevalence of 12 in 10,000 .
the genetic classification distinguishes the disorders due to defects in mtdna from those due to defects in nuclear dna .
the effects of mutations which affect the respiratory chain may be multisystemic , with possible involvement of visual and auditory pathways , heart , central nervous system , and skeletal muscle .
the  red flags  of mitochondrial diseases are myopathic signs and symptoms ( including fatigue and exercise intolerance ) , eyelid ptosis , ophthalmoparesis , axonal multifocal neuropathy , sensorineural hearing loss , pigmentary retinopathy , optic neuropathy , diabetes mellitus , hypertrophic cardiomyopathy , migraine , short stature .
experienced fatigue may be defined as an overwhelming sense of tiredness , lack of energy and feeling of exhaustion .
more specifically , muscle fatigue with exercise intolerance is a multifactorial process characterized by failure to maintain an expected level of force during sustained or repeated muscle contraction , and is considered a common symptom of mitochondrial diseases .
it is putatively due to an increased skeletal muscle dependence on anaerobic metabolism , with increased lactate and free radical generation , phosphocreatine ( pcr ) depletion , reduced oxygen extraction . at the whole body level , this is characterized by a reduction in maximal oxygen consumption ( vo2 ) with excessive carbon dioxide production ( vco2 ) , increased rating of perceived exertion and hyperdynamic circulatory response at a given exercise intensity .
classically , the characterization of exercise intolerance is performed using cycloergometry with measurements of vo2 , vco2 , respiratory exchange ratio , heart rate , minute ventilation , rating of perceived exertion , and cardiac output .
taivassalo and co - workers   evaluated oxidative capacity and circulatory and ventilatory responses to maximal cycle exercise in 40 patients with biochemically and/or molecularly defined mitochondrial myopathies associated with variable degrees of exercise tolerance , comparing those responses with healthy sedentary individuals results . in mitochondrial patients ,
mean peak work capacity and vo2 were significantly lower than in controls , but the range was quite broad .
oxidative capacity in patients was limited by the ability of muscle to extract available oxygen from blood , as indicated by a linear correlation between peak vo2 and peak systemic arterovenous o2 difference . in the patients group ,
the increase in cardiac output relative to vo2 and ventilation was increased compared to controls . in patients with heteroplasmic mtdna mutations ,
an inverse relationship between the proportion of skeletal muscle mutant mtdna and peak extraction of available o2 during exercise was observed .
another study   showed that the severity of oxidative impairment ( as assessed during cycloergometer exercise ) closely correlated with venous o2 levels during forearm exercise , which resulted paradoxically increased in these patients .
this may reflect a blunted ability of working muscle to extract o2 , resulting in high o2 delivery relative to use , high tissue o2 content , and elevated o2 levels in venous effluent . from a biochemical perspective , in patients with suspected mitochondrial disease , lactate increase after effort is commonly measured and has diagnostic use .
however , the role of lactate in the development of exercise intolerance in these patients is unclear . in a double - blinded
, placebo - controlled , crossover study in seven patients with mitochondrial myopathy , lowering of lactate with dichloroacetate could not improve exercise tolerance and oxidative capacity , suggesting that lactate is not the primary cause of exercise intolerance .
a biochemical study could not demonstrate any difference between healthy controls and mitochondrial patients ; consecutive 60-min microdialysis samples were taken from the tibialis anterior muscle in eleven healthy subjects and four patients with mitochondrial myopathy , before and after sustained isometric foot dorsi - flexions . before exercise , mean concentrations of lactate , pyruvate , hypoxanthine , urate , aspartate , and glutamate
after exercise , both groups showed increased concentrations of lactate , pyruvate , and urate , decreased hypoxanthine , and no change in aspartate and glutamate .
exercise - induced increase in integrated electromyogram amplitude and rated subjective fatigue were correlated to increased post - exercise lactate concentrations , with no differences between the two groups .
this experimental apparatus could allow the detection and monitoring of biochemical changes in the interstitial space , but larger studies should be performed .
another approach to measure fatigue is the use of magnetic resonance spectroscopy ( mrs ) , a frequency analysis of the mr signal that allows an evaluation of brain and muscle metabolism in vivo .
phosphorous ( 31p ) mrs measures pcr and inorganic phosphate ( pi ) fluctuations during muscle exercise , thus monitoring oxidative metabolism .
the most useful indicators of mitochondrial disease are combined low pcr / pi ratio at rest and low post - exercise recovery , and delay in post exercise adenosine diphosphate ( adp ) recovery .
nevertheless , 31p mrs of skeletal muscle does not seem to be a sensitive diagnostic test for mitochondrial myopathy . in a study of seven patients with single large - scale deletion , nine with mtdna point mutations and 14 healthy subjects , pcr / pi and atp production after exercise was similar in patients and healthy subjects .
for these reasons , muscular 31p mrs is still experimental in clinical practice , but could potentially be a useful tool for monitoring the response to therapies .
the treatment of mitochondrial diseases is still inadequate , despite great progress in the molecular understanding of these disorders .
therapies that have been attempted include respiratory chain cofactors and other metabolites and antioxidants , but their role in the treatment of the majority of these patients remains unclear
. however , a randomized trial reported that 60  days of coenzyme q10 ( 1200  mg / day ) treatment had minor but significant positive effects on cycle exercise aerobic capacity ( with significant increase in vo2 ) and post - exercise lactate , even though it did not affect other clinically relevant variables such as strength or resting lactate .
several studies have found that supervised aerobic activity can improve exercise capacity , reduce lactate and improve adp recovery kinetics using mrs .
the effect of 12  weeks cycle training on exercise capacity , quality of life and underlying molecular and cellular events have been studied in 20 mitochondrial patients and 13 healthy subjects . after the training , maximum vo2 and muscle citrate synthase increased in patients and healthy controls , while mtdna quantity in muscle only increased in the patient group .
therefore , aerobic training could efficiently improve oxidative capacity in patients with mitochondrial myopathy , and regular aerobic exercise may be recommended in these subjects .
based on the database of the  nation - wide italian collaborative network of mitochondrial diseases  , we preliminarily reviewed the clinical data of the 1164 histologically , biochemically and/or molecularly defined patients present in our database ( june 18th , 2012 ) and followed in the different centers , with special regard to exercise intolerance .
the database establishment ( and its use for scientific purposes ) was permitted by the local ethical committees of the single centers , which obtained the patients written consent , and has been performed in accordance with the ethical standards laid down in the 1964 declaration of helsinki .
comparisons of proportions have been performed by chi - square test . a p value < 0.05 was considered as significant .
the clinical picture was fully available for 1100 patients ( mean age at onset 24.4    20.5  years ; age at last evaluation 39.8    22.3  years ; females 51.0% ; childhood onset [ before age 16-yrs ] 43.8% ) .
exercise intolerance was part of the clinical picture in 222/1100 patients ( 20.2% ) , being the fourth clinical manifestation in term of frequency in these patients after ptosis / ophthalmoparesis , muscle weakness and hearing loss .
in 108 of them , exercise intolerance was one of the presenting symptoms at the onset of the disease . in order to understand
if the presence ( or absence ) of exercise intolerance was linked with specific molecular or pathological features , the patients of the registry have been divided in two groups , with and without exercise intolerance .
age at onset , age at last evaluation and gender ratio did not significantly differ between the two groups . from a genotype - based approach ( table 1 ) , the common mtdna a3243 g mutation associated with melas ( mitochondrial encephalomyopathy with lactic acidosis and stroke - like episodes ) and other clinical phenotypes , was less present in the group without than one with exercise intolerance ( p  <  0.0005 ) .
exercise intolerance was reported in 33/95 ( 34.7% ) of the a3243 g patients of our database .
( myoclonic epilepsy with ragged red fibers ) mutation , showed the same frequency in the two groups . from the opposite perspective , 9/36 ( 25.0% )
the mtdna t8993c mutation , associated with narp ( neuropathy , ataxia , retinitis pigmentosa ) and with maternally - inherited leigh syndrome , was more common in the group without than with exercise intolerance , but the difference did not reach statistical significance . only 1/20 of
as expected , patients with genetically - confirmed leber hereditary optic neuropathy ( lhon ) were far more common in the group without than with intolerance ( p  <  0.0001 ) .
the same was observed for opa1 gene mutations , the most common cause of autosomal dominant optic atrophy ( adoa ) .
polg gene mutations had the same frequency in the two groups ; 8/41 ( 19.8% ) polg patients complained of exercise intolerance . from a phenotype - based approach ,
patients with peo phenotype were more common in the group with exercise intolerance ( 87/222 [ 39.2% ] versus 247/878 [ 28.1% ] , p  < 
leigh syndrome was more common in the group without exercise intolerance ( 72/878 [ 8.2% ] versus 5/222 [ 2.3% ] , p  <  0.005 ) .
probably , in these young patients , the subtle symptom  exercise intolerance  is hidden by the devastating neurodegenerative phenotype . from a clinical perspective , as expected , muscle weakness was less frequent in the patients without ( 255/878 , 29.0% ) than with ( 155/222 , 69.8% ) exercise intolerance ( p  <  0.0001 ) .
the same finding was also observed when considering all the other myopathic signs included in our database : muscle pain ( 6.5% versus 27.0% , p 
<  0.0001 ) , muscle wasting ( 14.6% versus 30.2% , p  <  0.0001 ) , eyelid ptosis / ophthalmoparesis ( 38.8% versus 58.6% , p  <  0.0001 ) , cardiomyopathy ( 4.9% versus 17.1% , p  <  0.0001 ) , increased plasma creatine kinase ( ck ) levels ( 12.6% versus 34.2% , p  <  0.0001 ) . in those patients in whom muscle biopsy has been performed , ragged red fibers were less common in the group without ( 311/484 , 64.3% ) than with ( 127/169 , 75.1% ) exercise intolerance ( p  <  0.05 )
the same was observed for cox ( cytochrome c oxidase)-negative fibers , with a stronger statistical significance ( 295/484 [ 61.0% ] versus 124/169 [ 73.4% ] ( p    0.005 ) . finally , considering the patients for whom plasma lactate levels were available ,
this biomarker was increased in 269/502 ( 53.6% ) patients without exercise intolerance and in 89/175 ( 50.9% ) patients with exercise intolerance ( p not significant ) .
exercise intolerance and fatigue are difficult to assess clinically and remain an elusive symptom , even in the neuromuscular setting .
new methods to quantify these rather common complaints are strongly needed in the clinical practice .
this symptom seems more strongly associated with specific mutations ( i.e. , a3243 g ) .
ck levels were increased in 34% of the patients with exercise intolerance , not confirming the notion that ck levels are normal in the great majority of mitochondrial patients .
moreover , all the other myopathic signs included in our database ( muscle pain , muscle wasting , eyelid ptosis / ophthalmoparesis , cardiomyopathy ) were associated with exercise intolerance .
ragged red fibers and , especially , cox - negative fibers were more frequent in the subjects with exercise intolerance , whereas lactate levels failed to predict the presence of exercise intolerance .
lactate is the most common marker of mitochondrial dysfunction in the clinical practice , but additional , possibly more reliable , markers are still strongly needed .
admittedly , this survey presents the typical limitations of all retrospective studies , and probably underestimates the real prevalence of exercise intolerance in patients with mitochondrial diseases , being a symptom that sometimes could be missed when not actively searched .
however , similar multicenter efforts are strongly needed for rare disorders such as mitochondrial diseases , and can prompt to more rigorous longitudinal studies .
multicenter studies are also needed to better characterize the clinical picture and natural history of these diseases , and identify pharmacological , physical , or other countermeasures capable to benefit the patients suffering with these chronic , still incurable disorders .
the nationwide italian collaborative network of mitochondrial diseases includes : bruno c , filosto m , lamperti c , martinelli d , moroni i , musumeci o , orsucci d , pegoraro e , santorelli fm , scarpelli m , sciacco m , spinazzi m , valentino ml , vercelli l.
fatigue and exercise intolerance are common symptoms of mitochondrial diseases , but difficult to be clinically assessed . 
 new methods to quantify these rather common complaints are strongly needed in the clinical practice . 
 coenzyme q10 administration and aerobic exercise may improve exercise intolerance , but more definite studies are still pending . 
 herein , we have revised  how to measure  and  how to treat  these symptoms of mitochondrial patients . 
 subsequently , we reviewed the clinical data of the 1164 confirmed mitochondrial patients present in the italian nation - wide database of mitochondrial disease , with special regard to exercise intolerance . 
 we observed that more of 20% of mitochondrial patients complain of exercise intolerance . 
 this symptom seems to be frequently associated with specific patient groups and/or genotypes . 
 ragged red fibers and cox - negative fibers are more often present in subjects with exercise intolerance , whereas lactate levels could not predict this symptom . 
 multicenter efforts are strongly needed for rare disorders such as mitochondrial diseases , and may represent the basis for more rigorous longitudinal studies .