Nerve Endings In Muscle Research Articles

Degeneration of proprioceptive sensory nerve endings in mice harboring amyotrophic lateral sclerosis–causing mutations

ABSTRACTAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily targets the motor system. Although much is known about the effects of ALS on motor neurons and glial cells, little is known about its effect on proprioceptive sensory neurons. This study examines proprioceptive sensory neurons in mice harboring mutations associated with ALS, in SOD1G93A and TDP43A315T transgenic mice. In both transgenic lines, we found fewer proprioceptive sensory neurons containing fluorescently tagged cholera toxin in their soma five days after injecting this retrograde tracer into the tibialis anterior muscle. We asked whether this is due to neuronal loss or selective degeneration of peripheral nerve endings. We found no difference in the total number and size of proprioceptive sensory neuron soma between symptomatic SOD1G93A and control mice. However, analysis of proprioceptive nerve endings in muscles revealed early and significant alterations at Ia/II proprioceptive nerve endings in muscle spindles before the symptomatic phase of the disease. Although these changes occur alongside those at α‐motor axons in SOD1G93A mice, Ia/II sensory nerve endings degenerate in the absence of obvious alterations in α‐motor axons in TDP43A315T transgenic mice. We next asked whether proprioceptive nerve endings are similarly affected in the spinal cord and found that nerve endings terminating on α‐motor neurons are affected during the symptomatic phase and after peripheral nerve endings begin to degenerate. Overall, we show that Ia/II proprioceptive sensory neurons are affected by ALS‐causing mutations, with pathological changes starting at their peripheral nerve endings. J. Comp. Neurol. 523:2477–2494, 2015. © 2015 Wiley Periodicals, Inc.

Degeneration of proprioceptive sensory nerve endings in mice harboring amyotrophic lateral sclerosis-causing mutations.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily targets the motor system. Although much is known about the effects of ALS on motor neurons and glial cells, little is known about its effect on proprioceptive sensory neurons. This study examines proprioceptive sensory neurons in mice harboring mutations associated with ALS, in SOD1(G93A) and TDP43(A315T) transgenic mice. In both transgenic lines, we found fewer proprioceptive sensory neurons containing fluorescently tagged cholera toxin in their soma five days after injecting this retrograde tracer into the tibialis anterior muscle. We asked whether this is due to neuronal loss or selective degeneration of peripheral nerve endings. We found no difference in the total number and size of proprioceptive sensory neuron soma between symptomatic SOD1(G93A) and control mice. However, analysis of proprioceptive nerve endings in muscles revealed early and significant alterations at Ia/II proprioceptive nerve endings in muscle spindles before the symptomatic phase of the disease. Although these changes occur alongside those at α-motor axons in SOD1(G93A) mice, Ia/II sensory nerve endings degenerate in the absence of obvious alterations in α-motor axons in TDP43(A315T) transgenic mice. We next asked whether proprioceptive nerve endings are similarly affected in the spinal cord and found that nerve endings terminating on α-motor neurons are affected during the symptomatic phase and after peripheral nerve endings begin to degenerate. Overall, we show that Ia/II proprioceptive sensory neurons are affected by ALS-causing mutations, with pathological changes starting at their peripheral nerve endings.

The pathogenesis of muscle pain.

Nociceptive nerve endings in muscles and other tissues are equipped with a multitude of receptor molecules for endogenous pain-producing and sensitizing agents. Particularly interesting molecules are the purinergic receptors, which can be activated by adenosine triphosphate (ATP), and the vanilloid receptor, which is sensitive to protons (low pH). The purinergic receptors are activated by tissue damage because cell necrosis is associated with the release of ATP. A low pH is present in many pathologic conditions such as ischemia and inflammation. At the spinal and medullar level, painful muscle lesions induce marked neuroplastic changes that result in hyperexcitability and hyperactivity of nociceptive neurons. This central sensitization is the basis for the spontaneous pain and hyperalgesia of patients. The transition from acute to chronic muscle pain is complete when the initially functional changes are transformed into structural ones. Patients with morphologic alterations in their nociceptive system are difficult to treat because the changes need time to normalize.

Incubation of Poliomyelitis as Calculated from the Time of Entry into the Central Nervous System via the Peripheral Nerve Pathways

A new theory of how poliovirus reaches the central nervous system (CNS)--that it enters at many peripheral nerve endings with passage along nerve pathways to the CNS, with limited dispersal in the CNS--is used in making predictions of incubation periods, and these are compared with data from the literature and with predictions from other theories. The virus transit speed along the nerve of 2.4 mm/h has been used in calculating the incubation time. The calculated incubation time for Cutter vaccinees is similar to the actual times reported, and the calculated minimal and maximal incubation times in humans are similar to the published ranges. Incubation times in different animals and for different paralyses are explained. The pathology of lesions in humans and the consequent paralyses are compatible with the model. Tonsillectomy-associated poliomyelitis is reviewed and discussed in relation to possible entry of virus from peripheral nerve endings in muscle. Increased lymphocyte concentrations in the muscle may account for continuing susceptibility after tonsillectomy. Severe paralysis following exercise is explained as an effect of increased blood supply to nerves in the CNS that has already been invaded by virus. In developing countries, the phenomenon of paralysis in the injected muscle a few hours after injection in febrile children may occur in a similar fashion. The entry of poliovirus from many sites at nerve endings in muscles is consistent with clinical, experimental, and pathologic data and provides an explanation of the incubation times and related phenomena of poliomyelitis.

Uniform staining of nerve endings in skeletal muscle with gold chloride.

Skeletal muscle, teased into strips several millimeters long and 1 mm or less thick, is fixed in a 3:1 mixture of lemon juice and formic acid until transparent. The tissue is compressed between folds of absorbent material to remove excess fixative and impregnated for 10 min in a volume of 1% gold chloride equal to the volume of muscle. After removing excess gold chloride, reduction is effected. Method a. Exposure to 25% formic acid in the dark for 6 hr. When intramuscular nerves are visible, the muscle is further teased with glass instruments. Reduction is continued for an additional 18 hr in 25% formic acid, and the tissue is cleared in glycerol for 24 hr. Method b. Exposure to intense artificial visible light while the tissue is just immersed in distilled water at 37° C. Colour develops in the nerve endings as in a photographic print. When nerves only are stained (approximately 0.5 hr), the lamp is removed and microdissection at room temperature commenced. When nerve endings in muscle spindles are just ...

Significance of the silent period of muscles.

THE most attractive theory of the silent period of muscle action potentials is that of Matthews1,2 (following a speculation of Fulton and Pi-Suner3). In his pioneer work on single nerve endings in muscle, he showed that during a twitch, at a time corresponding to the silent period, there was a pause in sensory discharge from the muscle spindles—the endings believed responsible for exciting postural muscular contractions through the stretch reflex. This cessation of excitatory impulses clearly explained the silent period in the motor discharge. Matthews pointed out that the arrangement of muscle spindles in parallel with the main contractile fibres (which is responsible for the pause during a twitch) formed a self-regulating device, or servo-mechanism, for controlling tonic contraction of the muscle. Increased load or the onset of muscular fatigue would cause elongation of the spindles, thereby reflexly calling up a greater contraction of the muscle tending to restore the system to its original length. The classical type of stretch reflex experiment discloses the static characteristics of the servo; the silent period is its transient response.

II.—Studies on the Pharmacological Action of Tetra-Alkyl-Ammonium Compounds.

In a paper on “The Pharmacological Action of Protocatechyl-tropeine,” communicated to the Society in 1909, I drew attention to the fact that this substance, when injected intravenously in certain doses produces transient paralysis of the respiration; and I mentioned further that Tappeiner had described a similar temporary cessation of the respiration after the intravenous injection of certain quaternary isoxazol and pyrazol compounds, and of tetra-methyl-ammonium chloride, and Pohl, after the intravenous injection of some quaternary papaverine derivatives. Tappeiner came to the conclusion that the effect was due to stimulation of the terminations of the fifth cranial nerve in the nose; that it was, in fact, of the nature of a Kratschmer-Hering reflex, since he was unable, in the case of methyl-phenylisoxazol-methochloride, to produce cessation of the respiration after anæsthetising the nasal mucous membrane with cocaine; and Iodlbauer, working in Tappeiner's laboratory, also found that anæsthetisation of the nasal mucous membrane prevented the cessation of the respiration produced by tetra-methyl-ammonium chloride. Pohl, on the other hand, was able to produce this temporary paralysis of the respiration after section of the ophthalmic branches of both fifth nerves, and consequently he concluded that the effect was due to an action on the respiratory centre. I came to the same conclusion, since the effect was still obtained with protocatechyl-tropeine after section of both fifth nerves in the base of the skull and after section of both phrenic nerves, and was not synchronous with the effect on the circulation or with the paresis of the nerve-endings in the muscles of the hind limbs. Further work with tetra-methyl-ammonium chloride, however—my stock of protocatechyl-tropeiue being exhausted,—showed that the effect was in large measure peripheral and due to a transient paresis of the nerve-endings in the respiratory muscles.

The stimulation of nerve-endings in muscle and the theory of receptive substances

Langley has shown that the stimulating action of nicotine upon muscle is prevented by curare and that this antagonism is exhibited also in muscles in which the nerve fibers have been removed by degeneration. This and other facts have led him to formulate the hypothesis of special receptive substances present in the muscle upon which these drugs and other chemical stimuli exert their action, and furthermore he ventures the generalization, in contradiction of the usual belief, that “in no case do chemical substances have a special action on nerve-endings.”The series of experiments here reported were made at the suggestion of Dr. J. W. Warren to test the above hypothesis. The gastrocnemius muscle of the frog was used and its reactions were studied after immersion in solutions of sodium sulphocyanide and potassium sulphocyanide. The following results were obtained.1. Action of potassium sulphocyanide.—This salt was used in hypertonic solutions (2 per cent. KCNS made up in a Ringer's mixture) and in isotonic s...