Membrane and Cell BiologyMembrane and Cell BiologyБиологические мембраны0233-47553034-5219The Russian Academy of Sciences36223810.7868/S3034521925060032ArticlesСТАТЬИResearch ArticleMorphofunctional Evaluation of Rat Leg Muscles under the Influence of Hindlimb Unloading, Tenotomy, and DenervationМОРФОФУНКЦИОНАЛЬНАЯ ОЦЕНКА МЫШЦ ГОЛЕНИ КРЫСЫ ПРИ ВЛИЯНИИ АНТИОРТОСТАТИЧЕСКОГО ВЫВЕШИВАНИЯ, ТЕНОТОМИИ И ДЕНЕРВАЦИИSabirovaD. E.СабироваД. Э.sabirova.dianka@list.ruShadrinaA. A.ШадринаА. А.-EremeevA. A.ЕремеевА. А.-KhairullinA. E.ХайруллинА. Е.-BaltinaT. V.БалтинаТ. В.-Kazan (Volga Region) Federal UniversityКазанский (Приволжский) федеральный университетSirius University of Science and Technology, Sirius Federal TerritoryНаучно-технологический университет «Сириус», Федеральная территория СириусKazan State Medical UniversityКазанский государственный медицинский университет15122025426VOL 42, NO6 (2025)ТОМ 42, №6 (2025)47548725122025Copyright ©; 2025, Russian Academy of SciencesCopyright ©; 2025, Российская академия наук2025Russian Academy of SciencesРоссийская академия наукhttps://journals.rcsi.science/0233-4755/article/view/362238

Skeletal muscle atrophy can develop under the influence of various factors related to their disuse, such as immobilization, denervation, or exposure to microgravity. The aim of this work was to conduct a morphological and functional assessment of skeletal muscles in disuse models in rats. The rats were randomly assigned to a control group and groups that underwent denervation, tenotomy, and hindlimb unloading. During the experiments, a decrease in the diameter of muscle fibers was revealed in all experimental groups. During tenotomy, there was a decrease in dystrophin immunosuppression. During hindlimb unloading, the dystrophin level decreased, but by day 35, recovery was observed in the gastrocnemius and anterior tibial muscles, while in the soleus it continued to fall. After denervation, the dystrophin content also decreased, but then increased, reaching control values for the soleus muscle by day 35. The level of neuronal NO-synthase significantly decreased in all experimental groups. The effects of denervation and tenotomy lead to pronounced changes in the contractile function of the soleus muscle in rats, which are in direct correlation with the development of atrophic processes.

Атрофия скелетных мышц может развиваться под влиянием различных факторов, связанных с их неиспользованием, таких как иммобилизация, денервация или пребывание в условиях микрогравитации. Целью работы являлось проведение морфологической и функциональной оценки камбаловидной, икроножной и передней большеберцовой мышц в моделях неиспользования у крыс. Крысы случайным образом были распределены на контрольную группу и группы, подвергшиеся денервации, тенотомии и антиортостатическому вывешиванию (АОВ). В ходе экспериментов было выявлено уменьшение диаметра мышечных волокон во всех экспериментальных группах. При тенотомии происходило снижение иммуноэкспрессии дистрофина. При АОВ уровень дистрофина снижался, однако к 35 сут наблюдалось восстановление в икроножной и передней большеберцовой мышцах, тогда как в камбаловидной уровень продолжал падать. После денервации содержание дистрофина также снижалось, но затем возрастало, достигая у камбаловидной мышцы контрольных значений к 35 сут. Уровень нейрональной NO-синтазы достоверно снижался во всех экспериментальных группы. Влияние денервации и тенотомии приводит к выраженным изменениям сократительной функции камбаловидной мышцы у крысы.

muscle atrophydystrophinneuronal NO-synthasehindlimb unloadingdenervationtenotomyмышечная атрофиядистрофиннейрональная NO-синтазаантиортостатическое вывешиваниеденервациятенотомияРабота выполнена в рамках программы «Стратегическое академическое лидерство Казанского федерального университета» (ПРИОРИТЕТ-2030).Pette D., Vrbová G. 2017. The Contribution of neuromuscular stimulation in elucidating muscle plasticity revisited. Eur. J. Transl. Myol. 27 (1), 6368.Kalyani R.R., Corriere M., Ferrucci L. 2014. Age-related and disease-related muscle loss: The effect of diabetes, obesity, and other diseases. Lancet Diabetes Endocrinol. 2 (10), 819–829.Atherton P.J., Greenhaff P.L., Phillips S.M., Bodine S.C., Adams C.M., Lang C.H. 2016. Control of skeletal muscle atrophy in response to disuse: Clinical/preclinical contentions and fallacies of evidence. Am. J. Physiol. Endocrinol. Metab. 311 (3), 594–604.Oikawa S.Y., Holloway T.M., Phillips S.M. 2019. The impact of step reduction on muscle health in aging: protein and exercise as countermeasures. Front. Nutr. 6, 75.Booth F.W., Gollnick P.D. 1983. Effects of disuse on the structure and function of skeletal muscle. Med. Sci. Sports Exerc. 15, 415–420.Jackman, R.W., Kandarian S.C. 2002. The molecular basis of skeletal muscle atrophy. Am. J. Physiol. Cell Physiol. 287 (3), 834–843.Mirzoev T.M. 2020.Skeletal muscle recovery from disuse atrophy: Protein turnover signaling andstrategies for accelerating muscle regrowth. Int. J. Mol. Sci. 21, 7940.Sartori R., Romanello V., Sandri M. 2021. Mechanisms of muscle atrophy and hypertrophy: Implications in health and disease. Nat Commun. 12 (1), 330.Michael K. 2000. Relationship of skeletal muscle atrophy to functional status: A systematic research review. Biol. Res. Nurs. 2, 117–131.Xi S., Yue S. 2003. Research progress of disuse muscle atrophy. Chin. J. Clin. Rehabil. 7, 710–714.Baltina T.V., Eremeev A.A., Pleshchinskii I.N. 2006. The state of the contralateral neuromotor apparatus of the rat in conditions of unilateral tenotomy. Neuroscience and Behavioral Physiology. 36 (4), 385–389.De Angelis C., Scarfo C., Falcinelli M., Perna E., Reda E., Ramacci M.T., Angelucci L. 1994. Acetyl-L-carnitine prevents agedependent structural alterations in rat peripheral nerves and promotes regeneration following sciatic nerve injury in young and senescent rats. Exp. Neurol. 128, 103–114.Morey-Holton E.R. 1979. Spaceflight and bone turnover: correlation with a new rat model of weightlessness. BioScience. 29, 168–172.Ильин Е.А., Новиков В.Е. 1980. Стенд для моделирования физиологических эффектов невесомости в лабораторных экспериментах с крысами. Косм. биол. и авиакосм. мед. 14 (3), 79–80.Саченков О.А., Семенова Е.В., Федянин А.О., Смирнова В.В., Балтина Т.В. 2022. Свидетельство о государственной регистрации ПЭВМ № 2022661168 Программа для анализа гистологических изображений мышечной ткани.Otsu N. 1979. A threshold selection method from gray-level histograms. IEEE Trans. Sys. Man. Cyber J. 9, 62–66.Meyer F. 1994. Topographic distance and watershed lines. Signal Processing. 38, 113–125.Гришин С.Н., Хайруллин А.Е., Зиганшин А.У., Ефимова Д.В. 2023. Патент на полезную модель № 216564 U1 Российская Федерация, МПК А61N 1/04, G09B 23/28. Всасывающий куль-то нерва электрод для электрической стимуляции: № 2022131919: заявл. 07.12.2022: опубл. 14.02.2023, заявитель Федеральное государственное бюджетное образовательное учреждение высшего образования "Казанский государственный медицинский университет" Министерства здравоохранения Российской Федерации.Fitts R.H., Riley D.R., Widrick J.J. 2000. Physiology of a microgravity environment invited review: microgravity and skeletal muscle. J. Appl. Physiol. 89, 823–839.Bonanni R., Cariati I., Marini M., Tarantino U., Tancredi V. 2023. Microgravity and musculoskeletal health: What strategies should be used for a great challenge? Life (Basel). 13 (7), 1423.Ohira Y., Jiang B., Roy R.R., Oganov V., Ilyina-Kakueva E., Marini J.F., Edgetron V.R. 1992. Rat soleus muscle fiber responses to 14 days of spaceflight and hindlimb suspension. J. Appl. Physiol. 73 (2), 51–57.Phillips S.M., McGlory C. 2014. Cross Talk proposal: The dominant mechanism causing disuse muscle atrophy is decreased protein synthesis. J. Physiol. 592, 5341–5343.Powers S.K. 2014. Can antioxidants protect against disuse muscle atrophy? Sports medicine. 44 (2), 155–165.Sandri M., Sandri C., Gilbert A., Skurk C., Calabria E., Picard A., Walsh K., Schiaffino S., Lecker S.H., Goldberg A.L. 2004. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell. 117 (3), 399–412.Jagoe R.T., Goldberg A.L. 2001. What do we really know about the ubiquitin-proteasome pathway in muscle atrophy? Curr. Opin. Clin. Nutr. Metab. Care. 4 (3), 183–190.Guo A., Li K., Tian H.C., Fan Z., Chen Q.N., Yang Y.F., Yu J., Wuy X., Xiao Q. 2021. FGF19 protects skeletal muscle against obesity-induced muscle atrophy, metabolic derangement and abnormal irisin levels via the AMPK/SIRT-1/PGC-α pathway. J. Cell Mol. Med. 25 (7), 3585–3600.Macpherson P.C., Wang X., Goldman D. 2011. Myogenin regulates denervation-dependent muscle atrophy in mouse oclus muscle. J. Cell Biochem. 112 (8), 2149–2159.Gao H., Li Y.F. 2018. Distinct signal transductions in fast- and slow-twitch muscles upon denervation. Physiol. Rep. 6 (4), 13606.Chockalingam P.S., Cholera R., Oak S.A., Zheng Y., Jarrett H.W., Thomason D.B. 2002. Dystrophin-glycoprotein complex and Ras and Rho GTPase signaling are altered in muscle atrophy. Am. J. Physiol. Cell Physiol. 288, 500–511.Zhang P., Li W., Liu H., Li J., Wang J., Li Y., Chen X., Yang Z., Fan M. 2014. Dystrophin involved in the susceptibility of slow muscles to hindlimb unloading via concomitant activation of TGF-β1/Smad3 signaling and ubiquitin-proteasome degradation in mice. Cell Biochem. Biophys. 70 (2), 1057–1067.Swiderski K., Brock C.J., Trieu J., Chee A., Thakur S.S., Baum D.M., Gregorevic P., Murphy K.T., Lynch G.S. 2021. Phosphorylation of ERK and dystrophin S3059 protects against inflammation-associated C2C12 myotube atrophy. Am. J. Physiol. Cell Physiol. 320 (6), 956–965.Bialek P., Morris C., Parkington J., St Andre M, Owens J., Yaworsky P., Secherman H., Jelinsky S.A. 2011. Distinct protein degradation profiles are induced by different disuse models of skeletal muscle atrophy. Physiol. Genomics. 43 (19), 1075–1086.Zhao J., Brault J.J., Schild A. 2007. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab. 6 (6), 472–483.Fareed M.U., Evenson A.R., Wei W., Menconi M., Poylin V., Petkova V., Pignol B., Hasselgren P.O. 2006. Treatment of rats with calpain inhibitors prevents sepsis-induced muscle proteolysis independent of atrogin-1/MAFbx and MuRF1 expression. Am. J. Physiol. Regul. Integr. 290 (6), 1589–1597.Aby K., Antony R., Eichholz M., Srinivasan R., Li Y. Enhanced pro-BDNF-p75NTR pathway activity in denervated skeletal muscle. 2021. Life Sci. 286, 20067.Baum O., Aaldijk D., Engeli A.L., Spree M., Summermatter S., Handschin C., Zakrzewicz A. 2018. Relation of nNOS isoforms to mitochondrial density and PGC-1alpha expression in striated muscles of mice. Nitric Oxide. 77, 35–43.Suzuki N., Motohashi N., Uezumi A., Fukada S., Yoshimura T., Itoyama Y., Aoki M., Miyagoe-Suzuki Y., Takeda S. 2007. NO production results in suspension-induced muscle atrophy through dislocation of neuronal NOS. J. Clin. Invest. 117 (9), 2468–2476.Gomes M.D., Lecker S.H., Jagoe R.T., Navon A., Goldberg A.L. 2001. Atrogin-1, a muscle-specific Fabox protein highly expressed during muscle atrophy. Proc. Natl. Acad. Sci. U.S.A. 98 (25), 14440–14445.Lawler J., Kunst M.M., Hord J.M. 2014. EUK-134 ameliorates nNOSμ translocation and skeletal muscle fiber atrophy during short-term mechanical unloading. Am. J. Physiol. Regul. Integr. Comp Physiol. 306 (7), 470–482.Orr A.W., Helmke B.P., Blackman B.R., Schwartz M.A. 2006. Mechanisms of mechanotransduction. Dev. Cell. 10 (1), 11–20.Ломоносова Ю.Н., Каламкаров Г.Р., Бугрова А.Е., Шевченко Т.Ф., Карташкина Н.Л., Лысенко Е.А., Шенкман Б.С., Немировская Т.Л. 2012. Роль NO-синтазы в регуляции белкового метаболизма растянутой m. Soleus крыс при функциональной разгрузке. Биохимия. 77 (2), 256–266.Brennan J.E., Chao D.S., Xia H., Aldape K., Bredt D.S. 1995. Nitric oxide synthase complexed with dystrophin and absent from skeletal muscle sarcolemma in Duchenne muscular dystrophy. Cell. 82 (5), 743–752.Ohlendieck K., Swandulla D. 2021. Complexity of skeletal muscle degeneration: multi-systems pathophysiology and organ crosstalk in dystrophinopathy. Pflugers Arch. 473 (12), 1813–1839.Foletta V.C., White L.J., Larsen A.E., Léger B., Russell A.P. 2011. The role and regulation of MAFbx/atrogin-1 and MuRF1 in skeletal muscle atrophy. Pflugers Arch. 461 (3), 325–335.McDonald K.S., Fitts R.H. 1993. Effect of hindlimb unweighting on single soleus fiber maximal shortening velocity and ATPase activity. J. Appl. Physiol. 74 (6), 2949–2957.Flick M., Hoppeler H. 2003. Molecular basis of skeletal muscle plasticity – from gene to form and function. Rev. Physiol. Biochem. Pharmacol. 146, 159–216.Gong H.M., Ma W., Regnier M., Irving T.C. 2022. Thick filament activation is different in fast- and slow-twitch skeletal muscle. J. Physiol. 600 (24), 5247–5266.Ma W., Lee K.H., Yang S., Irving T.C., Craig R. 2019. Lattice arrangement of myosin filaments correlates with fiber type in rat skeletal muscle. J. Gen. Physiol. 151 (12), 1404–1412.Wilkinson D.J., Piasecki M., Atherton P.J. 2018. The age-related loss of skeletal muscle mass and function: Measurement and physiology of muscle fibre atrophy and muscle fibre loss in humans. Ageing Res. Rev. 47 (4), 123–123.Pierantozzi E., Szentesi P., Paolini C., Dienes B. 2022. Impaired intracellular Ca2+ dynamics, M-band and sarcomere fragility in skeletal muscles of obscurin KO mice. Int. J. Mol. Sci. 23 (3), 1319.