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Glycation is a series of non-enzymatic reactions initiated by addition of reducing sugars to epsilon-amino group of lysine residues and alpha-amino group of the N terminus of proteins, leading to the formation of advanced glycation end products (AGE). It is thought to be involved in aging and various neurodegenerative conditions. In the present study using anti-1-hexitol-lysine (1-HL) antibody, Amadori product, an early glycation product, was detected in axonal spheroids in the anterior horn of amyotrophic lateral sclerosis and in atrophic neurons of spinobulbar muscular atrophy (SBMA, Kennedy disease with abnormally expanded triplet repeats in androgen receptor gene) but not in other regions of the central nervous system. Furthermore, Amadori product was undetectable in the tissues from age-matched controls. Thus, 1-HL formation could not reflect physiological aging.
When muscles lose neural drive, they atrophy rapidly. Neuromuscular electrical stimulation (NMS) has been used in attempts to prevent or reverse the atrophy, but optimal stimulation programs and parameters are not well defined. In this study, we investigated the effects of four different stimulation patterns on disuse atrophy produced in the tibialis anterior, lateral gastrocnemius, and soleus muscles of rats paralyzed with tetrodotoxin for seven days. Stimulation paradigms differed from one another by their stimulation frequency (2 or 10 pulses/s) and by their stimulation period (2 or 10 h a day). Results showed that stimulation with 2 pulses/s, paradigms were more effective at preventing disuse muscle atrophy than higher-frequency stimulation. The most marked difference was in the slow soleus muscle, which had only 10% mean atrophy when stimulated at 2 pulses/s for 10 h, compared to 26% atrophy when stimulated at 10 pulses/s for either 2 or 10 h and 32% atrophy in unstimulated, paralyzed controls. The level of atrophic change was not correlated with the levels of serum creatine kinase, used as an index of muscle damage. Results suggest that remediation of disuse atrophy may be accomplished using unphysiologically low rates of motor-unit activation despite the relatively low force produced by such unfused contractions. This may have significant implications for the design of therapies for muscle paralysis consequent to upper-motoneuron lesions.
Muscle atrophy commonly occurs as a consequence of prolonged muscle inactivity, as observed after cast immobilization, bed rest or space flights. The molecular mechanisms responsible for muscle atrophy are still unknown, but a role has been proposed for altered permeability of the sarcolemma and of the surrounding connective tissue. Matrix metallo-proteinases (MMPs) are a family of enzymes with proteolytic activity toward a number of extracellular matrix (ECM) components; they are inhibited by tissue inhibitors of MMPs (TIMPs). In a rat tail-suspension experimental model, we show that after fourteen days of non-weight bearing there is increased expression of MMP-2 in the atrophic soleus and gastrocnemius and decreased expression of TIMP-2. In the same experimental model the expression of Collagen I and Collagen IV, two main ECM components present in the muscles, was reduced and unevenly distributed in unloaded animals. The difference was more evident in the soleus than in the gastrocnemius muscle. This suggests that muscle disuse induces a proteolytic imbalance, which could be responsible for the breakdown of basal lamina structures such as Collagen I and Collagen IV, and that this leads to an altered permeability with consequent atrophy. In conclusion, an MMP-2/TIMP-2 imbalance could have a role in the mechanism underlying muscle disuse atrophy; more studies are needed to expand our molecular knowledge on this issue and to explore the possibility of targeting the proteolytic imbalance with MMP inhibitors.
The loss of normal weight-bearing activity, which occurs during bed rest, limb immobilization, and spaceflight, stimulates a catabolic response within the musculoskeletal system, which results in a loss of skeletal muscle mass and bone mineral. The mechanism by which loading of muscle and bone is sensed and translated into signals controlling tissue formation remains a major question in the field of musculoskeletal research. In this investigation, we have examined the ability of two potentially anti-atrophic proteins, IGF-I and Shh, to inhibit disuse atrophy within muscle and bone, when electroporated into skeletal muscle. We have found that electroporation and ectopic expression of IGF-I and/or Shh within the gastrocnemius/soleus muscle significantly stimulated muscle fiber hypertrophy and increases in muscle size. In addition, we report that electroporation and ectopic expression of IGF-I and/or Shh within the gastrocnemius/soleus muscle attenuated the lost of muscle fiber area, muscle mass, and muscle mass density that normally occurs during disuse muscle atrophy. Finally, we found that ectopic expression of IGF-I and Shh within the gastrocnemius/soleus muscle inhibits parameters of osteopenia within the tibia and fibula associated with hindlimb unloading. These results support the theory that skeletal muscle can regulate bone maintenance and could offer potentially novel and efficient therapeutic options for attenuating muscle and bone atrophy during aging, illness and spaceflight.
We retrospectively reviewed 118 muscle biopsy specimens from 113 patients with clinical and/or biochemical evidence of mitochondrial cytopathy. Light microscopic evaluation revealed histologic abnormalities in 65 specimens. The most common histologic findings included angular atrophic esterase-positive muscle fibers, type II muscle atrophy, regenerating muscle fibers, and scattered cytochrome-oxidase deficient fibers. Ragged red fibers were noted in 3 specimens on a Gomori trichrome stain. Electron microscopic evaluation was performed in 113 muscle specimens, and in 34, no abnormalities were identified. Increased numbers of mitochondria, particularly in the subsarcolemmal region, were identified in 54 specimens. Increased mitochondrial size was seen in 8 specimens and paracrystalline mitochondrial inclusions in 3. Other ultrastructural findings included focally increased glycogen deposition, focal Z-band streaming, and focally increased lipid accumulation. For 39 cases, concomitant skin biopsy specimens were available; abnormalities were identified by electron microscopy in 12. The majority of biopsy specimens demonstrated some light or electron microscopic abnormality. Specific histologic findings suggestive of mitochondrial abnormalities (partial cytochrome oxidase deficiency, ragged red fibers) were noted in a minority of cases. Ultrastructural evidence of mitochondrial abnormalities was noted in the majority of cases.
Impaired axonal transport has been postulated to play a role in the pathophysiology of multiple neurodegenerative disorders. In this report, we describe the results of clinical and neuropathological studies in a family with an inherited form of motor neuron disease caused by mutation in the p150Glued subunit of dynactin, a microtubule motor protein essential for retrograde axonal transport. Affected family members had a distinct clinical phenotype characterized by early bilateral vocal fold paralysis affecting the adductor and abductor laryngeal muscles. They later experienced weakness and atrophy in the face, hands, and distal legs. The extremity involvement was greater in the hands than in the legs, and it had a particular predilection for the thenar muscles. No clinical or electrophysiological sensory abnormality existed; however, skin biopsy results showed morphological abnormalities of epidermal nerve fibers. An autopsy study of one patient showed motor neuron degeneration and axonal loss in the ventral horn of the spinal cord and hypoglossal nucleus of the medulla. Immunohistochemistry showed abnormal inclusions of dynactin and dynein in motor neurons. This mutation of dynactin, a ubiquitously expressed protein, causes a unique pattern of motor neuron degeneration that is associated with the accumulation of dynein and dynactin in neuronal inclusions.
To date, nine polyglutamine disorders have been characterised, including Huntington's disease (HD), spinobulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA), and spinocerebellar ataxias 1, 2, 3, 6, 7 and 17 (SCAs). Although knockout and transgenic mouse experiments suggest that a toxic gain of function is central to neuronal death in these diseases (with the probable exception of SCA6), the exact mechanisms of neurotoxicity remain contentious. A further conundrum is the characteristic distribution of neuronal damage in each disease, despite ubiquitous expression of the abnormal proteins. One mechanism that could possibly underlie the specific distribution of neuronal toxicity is proteolytic cleavage of the full-length expanded polyglutamine tract-containing proteins. There is evidence found in vitro or in vivo (or both) of proteolytic cleavage in HD, SBMA, DRPLA, and SCAs 2, 3, and 7. In HD, cleavage has been demonstrated to be regionally specific, occurring as a result of caspase activation. These diseases are also characterised by development of intraneuronal aggregates of the abnormal protein that co-localise with components of the ubiquitin-proteasome pathway. It remains unclear whether these aggregates are pathogenic or merely disease markers; however, at least in the case of ataxin-3, cleavage promotes aggregation. Inhibition of specific proteases constitutes a potential therapeutic approach in these diseases.
Chronic denervation syndromes such as the post-polio syndrome are associated with progressive muscle weakness and fatigue after motoneuron death. Neither the etiology nor the management of these syndromes is clear. To address this issue, we partially denervated rat hindlimb muscles for 1 or 12 months and examined whether chronically enlarged motor units (MUs) become destabilized with time and further destabilized by daily running on exercise wheels. MU enlargement, measured electrophysiologically and morphologically was significantly reduced at 12 months in extensively denervated muscles, and to a lesser extent in moderately denervated muscles, as compared to the findings at 1 month. A 1-month period of running exercise further reduced the size of the chronically enlarged MUs in the extensively denervated muscles. We have therefore (1) successfully established a rat model of time-related MU size reduction, in which destabilization of chronically enlarged MUs results in loss of axonal terminals, and (2) demonstrated that nonphysiological activity has small but significant effects of further destabilizing the chronically enlarged MUs.
The relationship between motor function and muscle strength in patients with spinal muscular atrophy (SMA) is still controversial. In 120 genetically proven SMA patients, aged 5 years or older, we measured muscle strength in the arms and legs by a hand-held dynamometer, forced vital capacity by a spirometer, and the time needed to walk 10 m, arise from the floor, and climb steps. SMA patients had markedly reduced muscle strength, approximating 20% of that predicted from age- and gender-matched normative data. Knee extensors were the weakest muscles in SMA patients. The young ambulant SMA patients performed better than adults in all the timed tests and had greater muscle strength on knee extension. This study shows a good relationship between motor ability and muscle strength in SMA and confirms that age-related loss of function in SMA is due to loss of muscle strength.
Spastic paresis follows chronic disruption of the central execution of volitional command. Motor function in patients with spastic paresis is subjected over time to three fundamental insults, of which the last two are avoidable: (1) the neural insult itself, which causes paresis, i.e., reduced voluntary motor unit recruitment; (2) the relative immobilization of the paretic body part, commonly imposed by the current care environment, which causes adaptive shortening of the muscles left in a shortened position and joint contracture; and (3) the chronic disuse of the paretic body part, which is typically self-imposed in most patients. Chronic disuse causes plastic rearrangements in the higher centers that further reduce the ability to voluntarily recruit motor units, i.e., that aggravate baseline paresis. Part I of this review focuses on the pathophysiology of the first two factors causing motor impairment in spastic paresis: the vicious cycle of paresis-disuse-paresis and the contracture in soft tissues.
We investigated the effects of the subacromial impingement syndrome (SIS) on shoulder sensory-motor control and maximal shoulder muscle strength. It was hypothesized that both would be impaired due to chronic shoulder pain associated with the syndrome. Nine subjects with unilateral SIS who remained physically active in spite of shoulder pain and nine healthy matched controls were examined to determine isometric and isokinetic submaximal shoulder-abduction force steadiness at target forces corresponding to 20%, 27.5%, and 35% of the maximal shoulder abductor torque, and maximal shoulder muscle strength (MVC). Electromyographic (EMG) activity was assessed using surface and intramuscular recordings from eight shoulder muscles. Force steadiness was impaired in SIS subjects during concentric contractions at the highest target force level only, with muscle activity largely unaffected. No between-group differences in shoulder MVC were observed. The present data suggest that shoulder sensory-motor control is only mildly impaired in subjects with SIS who are able to continue with upper body physical activity in spite of shoulder pain. Thus, physical activity should be continued by patients with SIS, if possible, to avoid the loss in neural and muscle functions associated with inactivity.
A 67-year-old man presented with myalgia, muscle atrophy, and a history of seronegative polyarthritis. Blood tests showed inflammation but no hematologic or immunologic abnormalities. Muscle biopsy revealed no vasculitis or myositis but Tropheryma whipplei was detected by polymerase chain reaction in muscle, blood, and duodenum specimens; this was confirmed by immunohistochemistry. Ceftriaxone led to clinical improvement. Although rare, Whipple's disease should be considered in the differential diagnosis of diffuse myopathy.