Nonsurgically induced disuse muscle atrophy and neuromuscular dysfunction upregulates alpha7 acetylcholine receptors

Abstract

Previous models of disuse have invariably used surgical methods require repetitive plaster casts applications. A method of disuse atrophy that does not require repetitive application is described. A modified plastic pipette tubing was applied to one hindlimb from thigh to foot resulting in immobilization of knee in extension and ankle in plantar flexion position. This method resulted in loss of soleus muscle mass to 11, 22, 39, and 45% at 3, 7, 14 and 21 days, respectively, in association with a significant decrease of tibialis twitch (25%) and tetanic tensions (26%) at 21 days, compared to contralateral side and/or sham immobilized controls. Immunohistochemical analysis of soleus using fluorescent α-bungarotoxin revealed a significant increase in the number of synapses per unit area (818+31 vs 433+16/mm2) and increase in muscle fibers per unit area (117 vs 83/mm2) most likely related to atrophy of muscle fibers bringing synapses closer. A three fold increase in alpha7 acetylcholine receptor (α7AChR) protein expression along with increased expression of α1AChR subunit on immobilized vs contralateral side was observed. The physiology and pharmacology of the novel finding of upregulation of α7AChRs with disuse requires further study.

Prevention of Burn-Induced Inflammatory Responses and Muscle Wasting by GTS-21, a Specific Agonist for α7 Nicotinic Acetylcholine Receptors

“…There is also a priori evidence that there is de novo expression of α7AChRs in muscle during muscle cachexia even in the absence of systemic inflammation. The upregulation of α7AChRs has been observed in skeletal muscle under certain catabolic condition including simple disuse (3) and motor nerve denervation (33). In view of the fact that these leucocytes and muscle express α7AChRs, we exploited the anti-inflammatory properties of α7AChRs to decrease inflammation in skeletal muscle.…”

GTS-21 attenuates loss of body mass, muscle mass, and function in rats having systemic inflammation with and without disuse atrophy

“…Most recently the de novo expression of another isoform, the α7nAChR (consisting of 5 homomeric α7 subunits only) has been described in muscle wasting conditions [32, 41, 43, 60]. The expression of α7nAChRs in normal mature muscle is minimal.…”

“…It has been clinically tested to decrease systemic inflammatory responses in a phase II clinical trial [34], as well as in schizophrenic, Alzheimer’s disease and attention-deficit hyperactivity disorder subjects [11, 29, 33, 50]. Disuse atrophy per se leads to inflammation and de novo expression of α7nAChRs in the wasting muscles, despite absence of systemic inflammation [32, 41]. The ability of the α7nAChR agonist GTS-21 to mitigate bacteria-induced systemic inflammatory responses and the skeletal muscle changes associated with it have not yet been tested.…”

“…was evidenced by increased methemoglobin (MetHb) levels (a surrogate for increased nitric oxide-levels), as well as increased α1-acid glycoprotein levels (an acute phase reactant protein), and decreased platelet and erythrocyte counts [9, 63]. Thus, there is a priori evidence that systemic inflammation and/or muscle wasting (disuse, sepsis and denervation) upregulate α7nAChRs both in muscle and leucocytes [30, 32, 41, 59]. Based on this evidence, the hypothesis tested in this study was that these upregulated α7nAChRs could be used to decrease systemic and local muscle inflammation, and therefore reverse the systemic inflammation-and/or disuse-induced muscle changes in the previously described rat model [9, 57].…”

Effect of Bone Marrow Mesenchymal Stem Cells on Satellite Cell Proliferation and Apoptosis in Immobilization-Induced Muscle Atrophy in Rats

“…Modified plastic casts were applied as described previously [16]. First, rats were anesthetized with 8% chloral hydrate (400 mg/kg, i.p.).…”