spinal cord injury ( sci ) refers to a series of spinal injuries caused directly or indirectly by external factors . depending on the segment affected by the injury , symptoms can range from motor and sensory dysfunction , muscle dystonia , and appearance of pathological reflexes . primary sci refers to the injury caused by the external forces acting directly or indirectly on the spinal cord . secondary sci refers to further damage caused by spinal cord compression , generated by edema , hematoma , compressive fractures , and broken intervertebral disc tissue . spinal cord injury is characterized by high morbidity , high cost , and young patient age and it often leads to severe permanent disability . sci not only affects the quality of patients ' lives , but it also adds a burden to the family and the society . the latest statistics showed that the global incidence of spinal cord injury is about 2361009/million people . in usa , about 250,000 people suffer from varying degrees of sci each year , with an annual rate of up to 2850/million . currently , there is a lack of effective clinical therapy to restore nerve function after sci [ 2 , 3 ] . instead , exercise has become the most important quantifiable means for functional recovery [ 4 , 5 ] , and its mechanism has been studied by both clinical doctors and basic researchers . here , we review recent researches on the mechanisms by which exercise training promotes functional recovery after sci . exercise not only directly strengthens paralyzed muscles and promotes motor function recovery but is also promoting brain remodeling , improves spinal microenvironment , and protects damaged distal motoneuron functions , at multiple levels and through various channels , thereby promoting functional recovery . in vitro studies have demonstrated that exercise can induce changes in the local neural circuitry , suggesting that afferent activity can activate cortical cells and promote nerve function remodeling . research on cortical reorganization after peripheral nerve injury also supports the idea of cerebral cortex plasticity . synaptic contact immaturity is implied by the following observations : the length increase and density decrease of dendritic spines within 7 days in adult rats with the semisection but restoring to normal after 28 days . it was shown that exercise after sci could improve functional prognosis and induce cerebral cortex recombination in the somatic region . for example , rats exercises after sci have shown a higher spontaneous firing rate of cortical neurons and enhanced forelimb sensory and sensorimotor stimulation ( i.e. , the forelimb motion projection area has been expanded to the lower limbs ) . in clinical studies , functional magnetic resonance imaging ( fmri ) in patients with cervical spinal cord injury has shown that functional improvement after exercise is related to the degree of activation of the motor cortex . studies using transcranial magnetic stimulation and electroencephalogram ( eeg ) recordings have further confirmed changes in the cortical sensorimotor area . compared with healthy subjects , the sensorimotor cortex area associated with the muscle tissue above the damaged region is expanded in sci patients . positron emission computed tomography ( pet ) studies have shown that , for sci patients , wrist strength exercises increase the activation of the representative area of the contralateral upper limb motor cortex . in addition , case studies have shown that , after complete c6 spinal cord injury , hand exercise can promote functional improvement and increase the representation of the hand muscles in the cerebral cortex . thus , after sci , the functional remodeling of the cerebral cortex occurs to promote functional recovery . moreover , exercise can affect post - sci remodeling of the brain function , through generation of systemic changes , such as improving blood circulation and neuroendocrine regulation and reducing spasticity . studies have confirmed that in animals with passive exercise training after spinal cord transection injury , the plasticity related neurotrophic factor , adenylate cyclase type 1 ( adcy1 ) , and brain - derived neurotrophic factor ( bndf ) increase in the somatosensory cortex , at levels significantly higher than in animals without training . bndf is important for neuronal growth and differentiation , and adcy1 is important for establishment of long - term synaptic plasticity . it was suggested that exercise training could promote brain function remodeling by inducing bdnf expression . graziano et al . found that , in animals with cycling training after thoracic spinal cord transection , tactile stimulation of the hind paw induced a neural response remapped to the cortical regions of front paws and forelegs under deep anesthesia . such training also improved the neurological cortical reorganization corresponding to the lower limbs , despite the interruption of afferent input from these limbs . active exercise can also increase the complexity dendrites in the dentate gyrus and the density of dendritic spines in rats , although the functional significance of these changes is not really clear . similar studies have demonstrated that treadmill training can promote axonal growth [ 19 , 20 ] and lesion proximal collateral sprouting and increase synaptic establishment . other similar findings in mature rat hippocampus have also shown that long - term treadmill training can increase the number of astrocytes and neural stem cells in the lower granular cell layer of the dentate gyrus . exercise stimulates the proliferation of endogenous neural stem cells and generates neurotrophic factors , such as bndf , which in turn regulate neural plasticity and improve motor function [ 22 , 23 ] . some studies have found that early exercise training after the corticospinal motor system injury can restore the contact of corticospinal tract ( cst ) and the movement projection of primary motor cortex ( m1 ) , thus increasing the number of cholinergic intermediate neurons in the ipsilateral and contralateral spinal cord and reducing the physical control disorder . therefore , passive exercise training of the areas below the spinal cord injury level can promote functional reorganization of the cortex . although brain function remodeling is an important mechanism for functional recovery after sci , excessive function remodeling can result in pathological consequences such as illusion of limb sensation   and neuropathic pain . therefore , further studies and a deeper understanding of the mechanisms of cortical remodeling are necessary in order to adopt the best strategy after the interruption of sensory afferent pathways . after sci , the distal neuron pathways undergo a wide range of chemical , electrophysiological , and structural changes , which result in spontaneous neurological remodeling . the effects of exercise training on the structure and function of the spinal cord post - sci include reconstruction of the neuronal structure ; cellular proliferation and differentiation ; activation of the metabolism and expression of neuronal substances and neurotrophic factors ; and regulation of the cellular electrophysiological function . experimental studies demonstrate that , after spinal cord injury , the length and density of the distal motor neuron dendrites and the overall neuron cell size are reduced , suggesting that sci can cause secondary damage to injured distal motor neurons . studies have even shown that , after thoracic sci in rats , exercise training can increase the axonal length of the soleus and tibialis anterior motor neurons , within the lumbar spinal cord . research using synaptophysin immunohistochemistry has shown that treadmill training can significantly increase the formation of the lumbar spinal synapses . similarly , stepping training after transection of new born rat spinal cord can cause significant pathway changes and increase motor neuron synapse activation by stimulating primary afferent fibers or white matter tracts . the expression of synaptophysin and psd-95 in the area surrounding the ventral horn of the spinal motor neurons is significantly higher in rats training on the treadmill than in the untrained group . exercise training can activate the motor neuron n - methyl - d - aspartate ( nmda ) receptor , by increasing the expression of bndf and trkb ( tyrosine kinase gene ) in spinal cord . nmda receptors further regulate neuronal survival , dendritic structure , synaptic plasticity , and neuronal circuits . active training can also increase the expression of neurotrophic factors and nestin - gfp around the ependymal area . this promotes ependymal cell proliferation and differentiation into neural precursor cells ( npc ) and further into oligodendrocytes and astrocytes , resulting in nerve regeneration and improved functional recovery . oligodendrocytes play a key role in leading and efficient signal transmission , and in maintaining and protecting a normal neuronal function . the immature oligodendrocytes markers , transferrin and cyclic nucleotide phosphohydrolase ( cnp ) , increased significantly after seven days of active training . the current consensus is that exercise can induce the neurotrophic factor bndf , insulin - like growth factor i ( igf - i ) , and vascular endothelial growth factor ( vegf ) , to promote spinal oligodendrocyte regeneration . active training can also elevate the levels of glial fibrillary acidic protein ( gfap ) , regulate the astrocytes aggregation , and promote astrocytes maturation and differentiation . in rats with treadmill training , the nucleolar area of motoneurons increases and becomes surrounded by basophilic granules . also , the staining intensity of glucose-6-phosphate dehydrogenase increases , indicating a boost in protein synthesis . after training , motoneurons can transport more axonal protein , through either forward or reverse transport , and thus improve the overall adaptability of the motor units . for example , synaptic protein snap25 links synaptic vesicles and presynaptic membrane and motor neuron axons transport synaptic proteins snap25 with high selectivity after training . other proteins , such as the enzyme malate dehydrogenase and the trophic factor calcitonin gene - related peptide , are present in higher amounts in the motoneurons . post - sci cycling training can also raise the amount of phosphocreatine - s6 ( p - s6 ) expressed by intermediate neurons and cause dendrites branching of motor neurons . exercise training can alter the electrophysiological properties of transacted spinal motoneurons , such as the hyperpolarization of resting membrane potential and voltage threshold , the speed increase of action potential , and the increase of after - hyperpolarization potential amplitude of action potential . studies have shown that depolarization of resting membrane potential ( rmp ) and spike trigger level ( stl ) occurs four weeks after complete transection of the thoracic spinal cord . after training , the rmp can become hyperpolarized , thus altering the inhibition of the rubrospinal tract on stepping and promoting functional recovery . stepping training can enhance muscle spindle afferent signals [ 42 , 43 ] , promote aspartate nmda receptors functioning , and increase the amplitude of the incoming signal of the motoneuron synapsis , causing an after - hyperpolarization in the action potential of motoneurons . in addition , the ventrolateral spinal cord white matter ( vlf ) can also induce changes in the electrophysiological activity of motoneurons . in rats with sci , a change in the after - hyperpolarization potential ( ahpd ) affects the rhythm , intensity , and duration of interneuron activity which affects the stepping function . passive exercise can enhance the magnitude of excitatory postsynaptic potentials ( epsp ) , increase the number of motoneurons that accept incoming signal , steer ahpd towards normal level , and restore normal stepping . ultra - microstructural analysis has shown that , after spinal cord transection , exercise training can increase the magnitude of gastrocnemius motor neuron ( mns ) excitatory postsynaptic potential ( epsp ) but has no significant effect on the inhibitory postsynaptic potential ( ipsp ) . spinal cord transection injury results in impaired stepping ability , causes reduced incoming signal from distal motoneuron synapses , enhances inhibitory effects , and thereby inhibits - and -mns activity . studies suggest that this may be related to the significantly more numerous inhibitory f - type enlarged terminals than in the excitatory s - type enlarged terminals . it could also be due to the structural changes occurring in the parallel c - type and m - type enlarged terminals of -mns cell bodies . exercise training can maintain a normal ratio between the excitatory s - type and the inhibitory f - type enlarged terminals of -mns and -mns , as such maintaining the ratio between excitatory and inhibitory signals to improve stepping function . after sci , paralyzed muscles exhibit decreased fiber diameter , reduced voluntary contraction force , decreased metabolism , delayed conversion of slow - twitch to fast - twitch fibers , and a cross - sectional area comprised mainly of type i fibers . currently , it is believed that skeletal muscle atrophy is characterized by lost [ 48 , 49 ] or apoptotic muscle fiber nuclei , suggesting that reduced myoglobin nuclei number leads to  nuclear apoptosis . the lost function characterizing muscle atrophy can be restored by several methods , primarily by inducing igf-1 , pax7 , and other molecules that promote myogenic cells ( satellite cells ) activation , proliferation , and differentiation and participating in muscle fibers ( muscle cells ) repair . studies have shown an increase in the soleus igf-1 protein levels after spinal cord injury . after treadmill training , soleus igf-1 shows additional increase , to activate proliferation and differentiation of satellite cells , and increase in the muscle fiber numbers . this implies that exercise training after sci can enhance satellite cell activity and promote muscle fiber formation . endurance training seems to increase terminal branching of nerves at the neuromuscular junction , although results are ambiguous . studies have shown that in cats with sci the expression the levels of myosin heavy chain ( mhc ) in the soleus can be restored after stepping training . after one week of weight - bearing stepping training after sci , the wet weight of the plantaris , medial / lateral gastrocnemius , soleus , and tibialis anterior muscles is significantly reduced . after three weeks of training , twitching and tonic tension peaks in the soleus muscle decrease significantly and the mhc expression in the extensor digitorum longus iix increases . by 10 weeks , the muscle wet weight , contractile properties , and mhc levels returne to baseline levels , except for lg / mg atrophy . although exercise training can improve neurological and skeletal muscle function by modulating the multilevel structures and function of the cerebral cortex , spinal cord , and skeletal muscle following spinal cord injury ( sci ) , current evidence suggests that exercise training has limited efficacy in improving motor function after sci in rodents or cats [ 5760 ] . such inadequate effects are believed to be attributed to insufficient neurotrophic factor production induced by training . therefore , in addition to exercise , more and more combinatory strategies have been investigated . many studies have shown that combined therapy can significantly promote the recovery after sci and relieve spasticity in rats compared to single treatments alone . current strategies focus on combinatorial effects of hematopoietic stem cells , neurotrophic factors , drugs , and electrical or magnetic stimulation . tashiro et al . showed that neural stem cell transplantation combined with treadmill training significantly improved spinal cord pathway conduction and increased central pattern generator activity , resulting in significantly improved motor function . dental pulp stem cell transplantation not only promoted motor function recovery but also significantly reduced lesion cavity and glial scar formation . the secretion of neurotrophic factors can be stimulated in the injured spinal cord by neural stem cell transplantation or exercise training [ 20 , 63 , 64 ] . direct neurotrophic factor application combined with exercise training can also promote functional recovery following sci . combined glial cell line - derived neurotrophic factor ( gdnf ) with early rehabilitation significantly reduced pathological changes and motor dysfunction in patients with sci . other neurotrophic factors such as brain - derived neurotrophic factor ( bdnf ) and neurotrophin-3 ( nt-3 ) can also significantly increase bbb scores , indicating improved functional recovery . the above studies suggest that trophic support from combinatorial treatment is an effective intervention to improve motor recovery after spinal cord injury . in addition , many studies have shown that electrical stimulation or magnetic stimulation combined with exercise training can influence motor function in sci patients . showed that spinal cord electrical stimulation combined with exercise training can induce sustained enhancement of synaptic transmission , thereby improving lumbar anatomical plasticity to promote motor function recovery . demonstrated that functional electrical stimulation combined with treadmill training could activate intraspinal circuits to improve gait control . after sci , load - bearing training combined with functional electrical stimulation can activate ankle flexion to prevent swing phase drag , also reduced swing phase time and improved limb coordination [ 69 , 70 ] . sensory stimulation of the tongue combined with specific training significantly improved the balance and gait of patients with incomplete sci . there are also reports that repetitive transcranial magnetic stimulation combined with plate training can significantly reduce lower limb stiffness in patients with sci . therefore , the combination of electrical or magnetic stimulation and exercise training could significantly improve motor function and maximize functional recovery , which provides a new perspective for clinical rehabilitation . intraperitoneal injection of fluoxetine combined with exercise training significantly increased bdnf in the hippocampus which promoted nerve regeneration and bbb score [ 73 , 74 ] . the combined use of meta - chlorophenylpiperazine ( mcpp ) and quipazine in sci not only improved bbb scores but also improved weight - bearing walking . the implantation of polypyrrole / iodine ( ppy / i ) can protect nerve tissue and promote functional recovery . . showed that combination therapy of chondroitinase abc , neurotrophic factors , and exercise training not only enhanced active motor function recovery by enhancing neuroanatomical plasticity of the descending tracts ( corticospinal tract and 5-ht pathway ) but also significantly reduced the astrocyte proliferation and inflammation around lesions . transplantation of schwann cells and olfactory ensheathing cells in the spinal cord of cats combined with chondroitinase abc treatment significantly improved motor function . drug therapy combined with exercise training is more favorable in the treatment of sci , suggesting that adjuvant drug treatment may have a better prognosis in sci patients in the clinic . in conclusion , exercise training can induce structural and functional changes in the cerebral cortex , spinal cord , and skeletal muscles , thus improving neural and muscular function following spinal cord injury . exercise appears to promote nerve regeneration with functional restoration , to induce corticospinal pathway connectivity , to maintain the functional status of spinal cord neurons , to activate skeletal muscle satellite cells , and to promote muscle fiber regeneration . exercise training combined with other treatments in sci is the future direction with the most promise . more research is needed to optimize the specific training parameters , such as intensity , duration , frequency , and so forth . also , the effect of exercise on sci secondary complications ( e.g. , chronic pain , bladder and gastrointestinal dysfunction , muscle mass loss , osteoporosis , pressure ulcers , joint and muscle pain , fatigue , sleep problems , depression , and temperature control loss ) is rarely discussed in literature and needs further exploration .
the exercise training is an effective therapy for spinal cord injury which has been applied to clinic . 
 traditionally , the exercise training has been considered to improve spinal cord function only through enhancement , compensation , and replacement of the remaining function of nerve and muscle . 
 recently , accumulating evidences indicated that exercise training can improve the function in different levels from end - effector organ such as skeletal muscle to cerebral cortex through reshaping skeletal muscle structure and muscle fiber type , regulating physiological and metabolic function of motor neurons in the spinal cord and remodeling function of the cerebral cortex . 
 we compiled published data collected in different animal models and clinical studies into a succinct review of the current state of knowledge .