Inhibitors of endopeptidase and angiotensin-converting enzyme lead to an amplification of the morphological changes and an upregulation of the substance P system in a muscle overuse model

Abstract

BackgroundWe have previously observed, in studies on an experimental overuse model, that the tachykinin system may be involved in the processes of muscle inflammation (myositis) and other muscle tissue alterations. To further evaluate the significance of tachykinins in these processes, we have used inhibitors of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), substances which are known to terminate the activity of various endogenously produced substances, including tachykinins.MethodsInjections of inhibitors of NEP and ACE, as well as the tachykinin substance P (SP), were given locally outside the tendon of the triceps surae muscle of rabbits subjected to marked overuse of this muscle. A control group was given NaCl injections. Evaluations were made at 1 week, a timepoint of overuse when only mild inflammation and limited changes in the muscle structure are noted in animals not treated with inhibitors. Both the soleus and gastrocnemius muscles were examined morphologically and with immunohistochemistry and enzyme immunoassay (EIA).ResultsA pronounced inflammation (myositis) and changes in the muscle fiber morphology, including muscle fiber necrosis, occurred in the overused muscles of animals given NEP and ACE inhibitors. The morphological changes were clearly more prominent than for animals subjected to overuse and NaCl injections (NaCl group). A marked SP-like expression, as well as a marked expression of the neurokinin-1 receptor (NK-1R) was found in the affected muscle tissue in response to injections of NEP and ACE inhibitors. The concentration of SP in the muscles was also higher than that for the NaCl group.ConclusionsThe observations show that the local injections of NEP and ACE inhibitors led to marked SP-like and NK-1R immunoreactions, increased SP concentrations, and an amplification of the morphological changes in the tissue. The injections of the inhibitors thus led to a more marked myositis process and an upregulation of the SP system. Endogenously produced substances, out of which the tachykinins conform to one substance family, may play a role in mediating effects in the tissue in a muscle that is subjected to pronounced overuse.

Genetic variation and exercise-induced muscle damage: implications for athletic performance, injury and ageing

“…In rabbit studies, inhibition of ACE revealed [in combination with neutral endopeptidase inhibitor] elevated muscle damage in a muscle overuse model induced by electrical stimulation every second day with four sessions in total (Song et al 2014 ), which is in line with the human findings of Yamin et al ( 2007 ). The muscle damage was accompanied by increased tachykinin, substance P and its preferred receptor neurokinin-1 receptor expression, which suggests that the tachykinin family may play a role in the inflammatory processes and pain (Song et al 2014 ; Dousset et al 2007 ). Substance P is widely expressed in human cells and tissues of the peripheral and central nervous systems but it is also found in extra neuronal cells and innervated tissues.…”

Neurokinin-1 Receptor as a potential drug target for COVID-19 treatment

“…NEP and ACE inhibitors administered intravenously along with SP, was found to cause muscle inflammation in rabbit after one week while only minimal changes were observed in the control group. Levels of SP and NK-1R was high in the inflamed muscles [39] .…”

Blocking substance P signaling reduces musculotendinous and dermal fibrosis and sensorimotor declines in a rat model of overuse injury

“…Substance P-NK-1R signaling has been implicated as inducing hypercellularity and collagen production in fibrotic tendinopathies and myositis, and has been proposed as a therapeutic target for their treatment, 32,37,38 although to our knowledge, these are first studies of this kind in an animal model of overuse-induced musculoskeletal disorders. We sought here to determine if Substance P-NK-1R signaling contributes to the early progression of sensorimotor declines and fibrogenic responses in multiple tissue types involved in performing a HRHF task using a specific NK1R antagonist (L-732,138) delivered intraperitoneally in the final 2 weeks of a 3-week task.…”

“…Substance P and NK1R increase in tendons and muscles with overuse, [32][33][34][35] and the Substance P-NK1R pathway has been implicated as an inducer of collagen production of over-use fibrotic tendinopathies. 32,37 The NK1R has been proposed as a therapeutic target for their treatment, 32,37,38 although this hypothesis has yet to be tested in vivo.…”