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Here, for the first time, we characterize the effects of SMase activity on human muscle fibre contractile function and assess skeletal muscle SMase activity in heart failure patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The effects of SMase on force production and intracellular Ca<jats:sup>2+<\/jats:sup> handling were investigated in single intact human muscle fibres. Additional mechanistic studies were performed in single mouse toe muscle fibres. RNA sequencing was performed in human muscle bundles exposed to SMase. Intramuscular SMase activity was measured from heart failure patients (<jats:italic>n<\/jats:italic>\u00a0=\u00a061, age 69\u00a0\u00b1\u00a00.8\u00a0years, NYHA III\u2010IV, ejection fraction 25\u00a0\u00b1\u00a01.0%, peak VO<jats:sub>2<\/jats:sub> 14.4\u00a0\u00b1\u00a00.6\u00a0mL\u00a0\u00d7\u00a0kg\u00a0\u00d7\u00a0min) and healthy age\u2010matched control subjects (<jats:italic>n<\/jats:italic>\u00a0=\u00a010, age 71\u00a0\u00b1\u00a02.2\u00a0years, ejection fraction 60\u00a0\u00b1\u00a01.2%, peak VO<jats:sub>2<\/jats:sub> 25.8\u00a0\u00b1\u00a01.1\u00a0mL\u00a0\u00d7\u00a0kg\u00a0\u00d7\u00a0min). SMase activity was related to circulatory factors known to be associated with progression and disease severity in heart failure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Sphingomyelinase reduced muscle fibre force production (\u221230%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) by impairing sarcoplasmic reticulum (SR) Ca<jats:sup>2+<\/jats:sup> release (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and reducing myofibrillar Ca<jats:sup>2+<\/jats:sup> sensitivity. In human muscle bundles exposed to SMase, RNA sequencing analysis revealed 180 and 291 genes as up\u2010regulated and down\u2010regulated, respectively, at a FDR of 1%. Gene\u2010set enrichment analysis identified \u2018proteasome degradation\u2019 as an up\u2010regulated pathway (average fold\u2010change 1.1, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.008), while the pathway \u2018cytoplasmic ribosomal proteins\u2019 (average fold\u2010change 0.8, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001) and factors involving proliferation of muscle cells (average fold\u2010change 0.8, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0002) where identified as down\u2010regulated. Intramuscular SMase activity was ~20% higher (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) in human heart failure patients than in age\u2010matched healthy controls and was positively correlated with markers of disease severity and progression, and with several circulating inflammatory proteins, including TNF\u2010receptor 1 and 2. In a longitudinal cohort of heart failure patients (<jats:italic>n<\/jats:italic>\u00a0=\u00a06, mean follow\u2010up time 2.5\u00a0\u00b1\u00a00.2\u00a0years), SMase activity was demonstrated to increase by 30% (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) with duration of disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The present findings implicate activation of skeletal muscle SMase as a mechanism underlying human heart failure\u2010related loss of muscle mass and function. Moreover, our findings strengthen the idea that SMase activation may underpin disease\u2010related loss of muscle mass and function in other clinical conditions, acting as a common patophysiological mechanism for the myopathy often reported in diseases associated with a systemic inflammatory response.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13029","type":"journal-article","created":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T06:20:31Z","timestamp":1658211631000},"page":"2551-2561","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Sphingomyelinase activity promotes atrophy and attenuates force in human muscle fibres and is elevated in heart failure patients"],"prefix":"10.1002","volume":"13","author":[{"given":"Karl","family":"Olsson","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Section of Clinical Physiology Karolinska Institutet  Huddinge 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Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2854-7262","authenticated-orcid":false,"given":"Eric","family":"Rullman","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Section of Clinical Physiology Karolinska Institutet and Department of Clinical Physiology Karolinska Univ Hospital  Huddinge Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,7,18]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehl541"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00065.2010"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.01269.2011"},{"key":"e_1_2_8_5_1","first-page":"530","article-title":"Sphingomyelinase promotes oxidant production and skeletal muscle contractile dysfunction through activation of NADPH 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