muscular dystrophies are hereditary disorders of skeletal muscle , but they may also involve the brain ( i.e. myotonic dystrophy ) . it is well known that myopathic patients have difficulties to support an excessive or long - term physical activity ; on the other hand the fatigability , met during the exercise of moderate or short - lived intensity and imposed by daily life , remains underestimated . fatigue can be an acute , i.e. the fatigue that follows an effort , or a chronic phenomenon . in the myopathic patient , fatigue can increase after muscle effort required for the realization of a task ( i.e. climbing stairs ) and/or the impossibility to realize this task . thus , the increase of physical exhaustion for the energetic expense and for a given exercise can be considered as cause of the acute fatigue . the loss of muscle force or the loss of capacity to maintain a certain level of force at maximum level is another cause of chronic fatigue . fatigue can be related to many mechanisms on several sites of the motor axis , ranging from the motor cortex to the muscle . the central fatigue implies that all the steps are localized upstream of the neuromuscular junction . the peripheral fatigue can be either due to coupling of excitement  contraction in muscle , availability of substrates or blood flow and exercise adaptation of vasodilatation by nitric oxide ( no ) as well as to the possible modifications of the intracellular environment and disruption of contractile apparatus [ 26 ] . the acute fatigue can be consequent to a load of excessive work in a short time and in myopathic patients after an eccentric exercise . there is often rupture of the sarcolemma and loss of sarcoplasmic enzymes , i.e. creatine kinase ( ck ) . nevertheless , if these loads are repeated and if the recovery and muscle regeneration is insufficient on the quantitative or qualitative levels , the patient can suffer from a generalized fatigue , characterized by permanent weakness and more chronic symptoms . this fatigue can also degenerate in chronic exhaustion i.e. a  burnout phenomenon  that constitutes the ultimate state in which the fatigue sensation can persist several weeks despite apparent recovery . multiple factors contribute to reduced motor ability and increased sedentary behavior , including muscle wasting secondary to the muscular dystrophy process itself ; fear of increased muscle damage leading to increasingly restricted mobility ; higher energy cost is partly caused by secondary contractures , biomechanical problems including ankle retraction , clumsy gait , poor balance , foot and knee deformities , and the increased body fat mass induced by disuse inactivity , muscle atrophy . in myotonic dystrophy patients , particularly in dm1 , where patients have an avoidant personality , reduced motivation is on turn accompanied by increased fatigue , depression , increased social barriers , and less social integration . moreover , several muscle patients have a marked reduction in pulmonary capacity and lower peak of oxygen consumption , or suffer from night desaturation symptoms that cause day time  sleepiness  and fatigue . both duchenne and becker muscular dystrophy patients might have decreased heart function , for a progressive cardiomyopathy , and decreased maximum ventilation . therefore , part of the reduced physical ability is directly due to the progressive muscle disease , but the disease also leads to physical deconditioning that can lead to increased risks for the co - morbidity caused by cardio - pulmonary complications . exhaustion during exercise and fatigue are among common presenting symptoms in medical consultations of dystrophic patients , and represent the most significant factors that negatively influence the quality of life for patients with muscle diseases . specific scales for evaluation of muscle fatigue are therefore useful in clinical trials and have to be added in clinical practice in patient management . our review covers the current state of the field , introduces new aspects of muscular dystrophy and myotonic dystrophy clinical characteristics and outlines recent developments in therapeutical efforts . quantitative assessment of muscle fatigue is not commonly carried out when evaluating myopathic patients , perhaps because of the complex nature and difficulty of defining and measuring fatigue . few studies have systematically examined the problem using objective measurement techniques ( mri with stir sequences , exercise induced fatigue , vascular effect on post - exercise activity by nitric oxide production , blood flow pre- and post - exercise ) . for instance , insufficient relief of local vasoconstriction in active muscle can lead to muscle edema and duchenne muscular dystrophy ( dmd ) and limb girdle muscular dystrophy ( lgmd ) patients show muscle edema on mri . furthermore , the variability of pathogenetic mechanisms underlying the various forms of muscular dystrophy is well known and it may play a different role in determining muscle changes . in myotonic dystrophy fatty degeneration and myxedema glycoprotein complex ( dgc ) that is composed of cytoskeletal proteins ( dystrophin , syntrophins ) , the dystroglycan complex and the sarcoglycan ( sg ) complex . the dgc provides a mechanical linkage between laminin in the extracellular matrix and the intracellular f - actin cytoskeleton . the structural and functional integrity of this connection is crucial to stabilize the sarcolemma during contractions . the sg complex is composed of four glycoproteins ( namely - , - , - , and -sg ) , whose mutant genes cause a group of autosomal recessive limb - girdle muscular dystrophies ( lgmd ) called  sarcoglycanopathies  ( lgmd2d , 2e , 2c and 2f , respectively ) . when one gene is mutated all the other sg components are secondarily reduced , the assembly of the sg complex is compromised , and the sarcolemma integrity and stability are lost a similar pathogenetic mechanism leads to dmd , which is caused by mutations in the dystrophin gene , while in becker dystrophy there is a residual abnormal dystrophin . the dgc has also signaling roles due to its interaction with other proteins including neuronal nitric oxide synthase ( nnos ) , which is anchored at the sarcolemma [ 411 ] . nitric oxide ( no ) is a messenger molecule that in muscle regulates development , contractility and blood flow . no is formed by nnos activity , which rapidly transduces signaling events in a calcium - dependent manner . in adult muscle , nnos is usually localized at the sarcolemma , the neuromuscular and myotendineous junctions , while in the soluble fraction , significant amounts of nnos are associated with the muscle phosphofructokinase isoform , although the nature of this interaction is unclear . regulation of nnos activity depends on the interaction with various proteins : it may be inhibited by caveolin-3 , a component of the dgc that might displace the activator calmodulin . one physiological role of nnos in normal muscle is the production of no that mediates the inhibition of sympathetic vasoconstriction . the secondary loss of nnos has been suggested to contribute to fiber degeneration in muscular dystrophies , both in duchenne and becker dystrophies , because the reduced production of nnos would reduce the normal protective action of no against local ischemia during contraction ( vascular hypothesis ) and increase the cellular susceptibility to superoxides ( oxidative stress hypothesis ) ( fig . 1 ) . muscle from dmd patients , dystrophin - deficient mdx mice and 1-syntrophin knock - out mice showed absent nnos at the sarcolemma , which however remained in the cytosol . absent sarcolemmal nnos was observed also in becker muscular dystrophy ( bmd ) with dystrophin gene deletions removing the central rod domain ( exons between 10 and 53 ) , a region which is crucial for the interaction between nnos and 1-syntrophin . the possibility that the loss of sarcolemmal nnos could be observed in disorders different from dystrophinopathies but having similar pathogenetic mechanism lead to an investigation in lgmd muscles . the sarcolemmal nnos was found to be normal in an early study on -sarcoglycanopathy , and reduced in a more extensive investigation on sarcoglycanopathies , suggesting that nnos defect might contribute to muscle pathology . among lgmd other than sarcoglycanopathies , only caveolinopathy ( due to caveolin-3 gene mutations ) has been investigated for nnos expression in muscle and it was found to be either normal in patients with the rippling muscle disease phenotype , or severely reduced in patients with lgmd phenotype . we analyzed the muscle biopsies from 32 patients affected with 7 different forms of molecularly defined lgmd and 5 patients with dmd , in order to investigate both the cytosolic nnos expression and its sarcolemmal localization . by evaluation of the role of nnos in muscle pathology and finally in disease progression , we found evidence supporting a role of nnos in modulating the disease phenotype , this could be of great importance for future therapeutic interventions in lgmd . one interesting and still controversial issue is whether the loss of sarcolemmal nnos , compounded with the defect of another muscle protein ( i.e. dystrophin or sarcoglycans ) might modulate the course of the disease . earlier studies demonstrated that normal nnos activity could reduce dystrophic symptoms : forced expression of nnos reduced muscle pathology in mdx mice ; nnos transgene in the myocardium of mdx mice prevented the ventricular fibrosis and greatly reduced myocarditis ; sarcolemmal nnos was restored by the use of minidystrophin vector in mdx mice . moreover , the level of nnos expression seemed to be inversely correlated with the severity of the disease in caveolinopathy and in bmd muscle ( table 1 ) . however , in animal models some experimental results suggested that a reduction of nos activity would not significantly contribute to the dystrophic pathology : mdx mice inbreeded with nos - null mutant mice showed no difference in muscle pathology compared with mdx mice ; nnos - null mice do not show muscular dystrophy ; 1-syntrophin knock - out mice with loss of sarcolemmal nnos did not show muscle degeneration . myotonic dystrophy type 1 ( dm1 ) is caused by an unstable expansion of ctg repeats ; the most common clinical features of dm1 include myotonia , muscle weakness and multisystemic involvement , i.e. heart and brain involvement . the majority of patients with dm1 complain of fatigue and day time sleepiness . in most dm1 patients fatigability is an abnormal sense of tiredness induced by mental or physical task . during motor tasks , fatigability is caused by the inability to sustain the required effort and may have in dm1 a central and/or peripheral component . central fatigue is a progressive reduction in voluntary muscle activation during exercise , related to cortical factors , while peripheral fatigue would result from an altered muscle function . various electrophysiological techniques have been developed to appraise the respective involvement of these different factors to explain fatigue in such pathological condition . despite the fact that exercise - induced fatigue is prominent in patients with dm1 , limiting daily living activities and thereby affecting quality of life , this phenomenon remains poorly documented . pathological studies of dm1 muscle have shown both preferential type 1 fiber atrophy and selective type 2 fiber loss , likely depending on the biopsied muscle and stage of disease severity , but the amount of fatigability is not proportional to muscle involvement or fiber atrophy . increased daytime sleepiness and fatigue are among the most frequent complaint in patients with dm1 . weak oro - pharyngeal and respiratory muscles leading to obstructive sleep apnea and alveolar hypoventilation have been regarded as causative factors of daytime sleepiness ; however , there is increasing evidence that tiredness primarily results from central nervous system dysfunction rather than progressive respiratory weakness . these considerations suggest that a study on parallel central nervous system and muscle involvement is needed to define the fatigability in dm1 patients . the only study linking nos and myotonic dystrophy suggests that although for induction of dystrophia myotonica protein kinase ( dmpk ) expression during myogenesis , nos is required , there is only a weak functional implication for such a generation and subsequent maintenance of dmpk expression . to understand the molecular basis of exercise induced fatigue response , genetically defined muscle disorders are a field of investigation . since secondary inflammation can be a feature of dystrophinopathy , one can speculate that fatigue is associated with muscle pain or to cytokine and ck release . during trials in dmd patients with deflazacort or prednisone , the exaggerated fatigue response in these patients was not attributed to inflammation or pain but to lack of muscle force and permanent weakness . loss of sarcolemma - localized nnos serves as a diagnostic indicator of substantial drop in activity in some forms of bmd or lgmd . when a patient is diagnosed as having a muscular dystrophy , questions arise about the prognosis , possible interventions and genetics . training or aerobic exercise programs might maximize strength and ventilatory assistance as well as cardiorespiratory function and prevent additional disuse atrophy . the benefit from strength training or aerobic exercise training in muscular dystrophies is not yet clear . the only two conditions in which strength training has been evaluated are myotonic dystrophy and facio - scapulo - humeral dystrophy . in myotonic dystrophy and facio - scapulo - humeral dystrophy , moderate intensity strength training appears not to do harm but there is insufficient evidence to conclude that it offers benefit . in order to further investigate the simultaneous cerebral and muscle impairment in dm1 , we recruited 24 dm1 patients ( 13 males , 11 females , mean age 34  years , age range 1567  years ) in our neuromuscular center and studied the severity of muscle involvement using a muscle impairment rating scale ( mirs ) . mirs scores varied between 1 and 5 : 2 patients scored 1 , 6 scored 2 , 9 scored 3 , 6 scored 4 , 1 scored 5 . we used muscle biopsy samples from routinely selected muscles : 11 from biceps brachii and 13 from vastus lateralis . cryosections underwent a panel of routine stains including haematoxylin - eosin , modified gomori trichrome , atp - ase at ph 4.3 and 9.4 , pas and oxidative stains . a quantitative and qualitative morphometric analysis was done for muscle fiber atrophy and hypertrophy factors . in dm1 the characteristic change in muscle on conventional h&e stain is variation and highly increased number of multiple internal nuclei in muscle fibers ( fig . 2 ) ; on immunohistochemistry slow type 1 fibers are on average smaller than fast type 2 fibers . we adopted , as a new parameter , the total white matter lesion load , which is obtained from the average score calculated in both hemispheres and separated the values obtained in four different classes . we also investigated the presence of other abnormalities : cranial hyperostosis , overdevelopment of the synus , ventriculomegaly ( fig . only four patients had normal mri imaging , while bilateral symmetrical focal or diffuse white matter abnormalities were found in 83% patients . diffuse symmetrical lesions were present in the insular regions in 15 patients ( 62% ) and in 12 of them a peculiar subcortical diffuse involvement of the polar region was detected . when we analyzed the distribution of ctg expansion classes , they correlated with lesion load by mri . also the distribution of muscle fiber atrophy factor classes was a function of ctg expansion ; however , there was no significant correlation between classes of atrophy factor and classes of the total white matter lesion load . we concluded therefore , that greater ctg expansion size is a confirmed risk factor for more extensive cerebral and muscle impairment . however , our study indicates that muscle and brain are independently involved in dm1 . as a consequence , we conclude that two distinct types of fatigue are possible in dm1 : a central fatigue due to cortical atrophy and white matter lesions , and a peripheral fatigue due to atrophy of muscle fibers . there is currently no effective therapy for dm1 ; mexiletine , however , has been shown to be useful to control myotonia . powerful and stable antisense oligonucleotides ( aon ) have been identified , most of them complementary to the cug nucleotide expansion in dm1 that reduce products on the mutant dmpk allele and diminish ribonuclear foci sequestering muscle blind like protein ( mbnl ) and therefore inducing multiple aberrant splicing . these aon in animal models enter very efficiently skeletal muscle ; however , the problem of the central component of fatigue in dm1 will not be solved by such an approach . absence or severe reduction of nnos expression at the sarcolemma was associated with severe early - onset muscular dystrophy in all cases and occurred with the presence of dilated cardiomyopathy in 2 of 3 sarcoglycanopathy patients , who were old enough to exhibit cardiomyopathy . limitation in the design studies in other muscular dystrophies prevents more general conclusions in these disorders . more research on fatigue is needed also in the field of muscular dystrophies and on the role of nnos , that when absent seems an adverse modulating factor . furthermore , experimental evidence in animal models of sarcoglycanopathies showed that transgenic mice with -sg and -sg deficiency had severe muscular dystrophy and cardiomyopathy , and that sg and dgc complexes were disrupted in skeletal , cardiac , and vascular smooth muscle , suggesting that a perturbation of vascular smooth muscle might be an additional mechanism that could contribute to the development of myopathy and cardiomyopathy . the no was found to be increased in regions of cardiac tissue damage and altered membrane permeability in sg mutant mice . the absence of sg complex in the vascular smooth muscle might lead either to structural changes or to an impairment of metabolic and signaling pathways involved in the microvascular dysfunction ; that is , high ca levels and disturbance of the nos pathway increase vasculature contractility , making cardiomyocytes more susceptible to intermittent ischemia . indeed , the use of vasodilator drugs has been shown to prevent the development of acute myocardial necrosis in animal models of - and -sarcoglycanopathy . the finding that absent sarcolemmal nnos can be found not only in some becker muscular dystrophy patients , but also in sarcoglycanopathies emphasizes the value of nnos immunohistochemical analysis in lgmd and provides further insights for future therapeutic interventions . in lgmd due to antioxidants that attenuate the superoxide attack and restore the bioactive no level and exogenous no donors or dietary addition of a nos substrate such as l - arginine , may be useful approaches for the treatment of these disorders . nos is a key enzyme in the production of no , a molecule that directly regulates vaso - relaxation and blood supply . the localization of nnos at the plasma membrane of muscle has recently been shown to prevent muscle fatigue after exercise . these results emphasize the value of nnos immunohistochemical analysis in muscular dystrophies and provide additional insights for future therapeutic interventions . lai et al .   showed that dystrophin anchors nnos to the sarcolemma through a direct interaction with dystrophin spectrin - like repeats 16 and 17 . furthermore , in another recently reported study of mouse models of muscular dystrophy , phosphodiesterase 5a inhibitors were used to treat the downstream ischemia that is associated with nnos mislocalization . collectively , these findings promise a series of therapeutic interventions based on our understanding of exercise - induced muscle fatigue and its role in muscle dystrophy .
fatigue is a frequent complaint in muscular dystrophies but it is yet not well defined or studied . we have examined the issue of muscle fatigue in a series of molecularly defined muscular dystrophies . a greater fatigability is seen in muscular dystrophy patients and can be an acute or chronic status . in duchenne 
 muscular dystrophy and beta - sarcoglycanopathy besides the alteration of dystrophin and/or sarcoglycan complex , a neuronal nitric oxide synthase depletion is frequently found and might correlate with post - exercise fatigability as well as with cardiac involvement . 
 therefore , it might be an important modulating factor of the severity of myopathy . 
 in myotonic dystrophy , fatigue is a common complaint : muscle is involved and type 1 atrophy is a frequent feature ; brain involvement and depressed mood might likely explain the extent of fatigue and daytime sleepiness commonly observed in these patients . 
 furthermore , in our observation in a series of 24 cases , muscle and brain can be independently involved in dm1 patients . 
 these observations have profound impact on the type of physical therapy to be prescribed in such patients .