» Articles » PMID: 35852046

Sphingomyelinase Activity Promotes Atrophy and Attenuates Force in Human Muscle Fibres and is Elevated in Heart Failure Patients

Abstract

Background: Activation of sphingomyelinase (SMase) as a result of a general inflammatory response has been implicated as a mechanism underlying disease-related loss of skeletal muscle mass and function in several clinical conditions including heart failure. 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.

Methods: The effects of SMase on force production and intracellular Ca 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 (n = 61, age 69 ± 0.8 years, NYHA III-IV, ejection fraction 25 ± 1.0%, peak VO 14.4 ± 0.6 mL × kg × min) and healthy age-matched control subjects (n = 10, age 71 ± 2.2 years, ejection fraction 60 ± 1.2%, peak VO 25.8 ± 1.1 mL × kg × min). SMase activity was related to circulatory factors known to be associated with progression and disease severity in heart failure.

Results: Sphingomyelinase reduced muscle fibre force production (-30%, P < 0.05) by impairing sarcoplasmic reticulum (SR) Ca release (P < 0.05) and reducing myofibrillar Ca sensitivity. In human muscle bundles exposed to SMase, RNA sequencing analysis revealed 180 and 291 genes as up-regulated and down-regulated, respectively, at a FDR of 1%. Gene-set enrichment analysis identified 'proteasome degradation' as an up-regulated pathway (average fold-change 1.1, P = 0.008), while the pathway 'cytoplasmic ribosomal proteins' (average fold-change 0.8, P < 0.0001) and factors involving proliferation of muscle cells (average fold-change 0.8, P = 0.0002) where identified as down-regulated. Intramuscular SMase activity was ~20% higher (P < 0.05) in human heart failure patients than in age-matched healthy controls and was positively correlated with markers of disease severity and progression, and with several circulating inflammatory proteins, including TNF-receptor 1 and 2. In a longitudinal cohort of heart failure patients (n = 6, mean follow-up time 2.5 ± 0.2 years), SMase activity was demonstrated to increase by 30% (P < 0.05) with duration of disease.

Conclusions: The present findings implicate activation of skeletal muscle SMase as a mechanism underlying human heart failure-related loss of muscle mass and function. Moreover, our findings strengthen the idea that SMase activation may underpin disease-related 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.

Citing Articles

25-Hydroxycholesterol modulates synaptic vesicle endocytosis at the mouse neuromuscular junction.

Kuznetsova E, Zakirjanova G, Tsentsevitsky A, Petrov A Pflugers Arch. 2025; 477(3):421-439.

PMID: 39786596 DOI: 10.1007/s00424-024-03058-0.


Mechanism of Purinergic Regulation of Neurotransmission in Mouse Neuromuscular Junction: The Role of Redox Signaling and Lipid Rafts.

Giniatullin A, Mukhutdinova K, Petrov A Neurochem Res. 2024; 49(8):2021-2037.

PMID: 38814360 DOI: 10.1007/s11064-024-04153-5.


β2-Adrenergic Regulation of the Neuromuscular Transmission and Its Lipid-Dependent Switch.

Gafurova C, Tsentsevitsky A, Fedorov N, Khaziev A, Malomouzh A, Petrov A Mol Neurobiol. 2024; 61(9):6805-6821.

PMID: 38353924 DOI: 10.1007/s12035-024-03991-2.


Sarcopenia and cardiovascular diseases: A systematic review and meta-analysis.

Zuo X, Li X, Tang K, Zhao R, Wu M, Wang Y J Cachexia Sarcopenia Muscle. 2023; 14(3):1183-1198.

PMID: 37002802 PMC: 10235887. DOI: 10.1002/jcsm.13221.


Sphingomyelinase activity promotes atrophy and attenuates force in human muscle fibres and is elevated in heart failure patients.

Olsson K, Cheng A, Al-Ameri M, Tardif N, Melin M, Rooyackers O J Cachexia Sarcopenia Muscle. 2022; 13(5):2551-2561.

PMID: 35852046 PMC: 9530516. DOI: 10.1002/jcsm.13029.

References
1.
von Haehling S, Coats A, Anker S . Ethical guidelines for publishing in the Journal of Cachexia, Sarcopenia and Muscle: update 2021. J Cachexia Sarcopenia Muscle. 2021; 12(6):2259-2261. PMC: 8718061. DOI: 10.1002/jcsm.12899. View

2.
De Larichaudy J, Zufferli A, Serra F, Isidori A, Naro F, Dessalle K . TNF-α- and tumor-induced skeletal muscle atrophy involves sphingolipid metabolism. Skelet Muscle. 2012; 2(1):2. PMC: 3344678. DOI: 10.1186/2044-5040-2-2. View

3.
Perreault C, Gonzalez-Serratos H, Litwin S, Sun X, Franzini-Armstrong C, Morgan J . Alterations in contractility and intracellular Ca2+ transients in isolated bundles of skeletal muscle fibers from rats with chronic heart failure. Circ Res. 1993; 73(2):405-12. DOI: 10.1161/01.res.73.2.405. View

4.
Cowart L . A novel role for sphingolipid metabolism in oxidant-mediated skeletal muscle fatigue. Focus on "Sphingomyelinase stimulates oxidant signaling to weaken skeletal muscle and promote fatigue". Am J Physiol Cell Physiol. 2010; 299(3):C549-51. DOI: 10.1152/ajpcell.00236.2010. View

5.
Grynkiewicz G, Poenie M, Tsien R . A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem. 1985; 260(6):3440-50. View