Reduced Synaptophysin-like 2 (MG29/SYPL2) Levels Mimic Age-Related Alterations in Skeletal Muscle Calcium Homeostasis and Lipid Signaling

Awad, Kamal; Huang, Jian; Aziz, Marian N.; Wang, Zhiying; Brotto, Leticia; Lee, Kyung Eun; Kim, Jongsoo; Karthikraj, Rajendiran; Gushchina, Liubov V.; Weisleder, Noah; Brotto, Marco

doi:10.3390/biom16070988

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Reduced Synaptophysin-like 2 (MG29/SYPL2) Levels Mimic Age-Related Alterations in Skeletal Muscle Calcium Homeostasis and Lipid Signaling

by

Kamal Awad

^1,†

,

Jian Huang

^1,†,

Marian N. Aziz

²,

Zhiying Wang

³,

Leticia Brotto

¹,

Kyung Eun Lee

⁴,

Jongsoo Kim

⁴,

Rajendiran Karthikraj

¹,

Liubov V. Gushchina

^5,6

,

Noah Weisleder

^7,* and

Marco Brotto

^1,*

¹

Bone-Muscle Research Center, College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX 76019, USA

²

Molecular Imaging Program, Department of Radiology, School of Medicine, Stanford University, Stanford, CA 94305, USA

³

Bristol Myers Squibb, Princeton, NJ 08540, USA

⁴

Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA

⁵

Jerry R. Mendell Center for Gene Therapy, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA

⁶

Department of Pediatrics, The Ohio State University, Columbus, OH 43210, USA

⁷

Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536, USA

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Biomolecules 2026, 16(7), 988; https://doi.org/10.3390/biom16070988 (registering DOI)

Submission received: 18 May 2026 / Revised: 25 June 2026 / Accepted: 29 June 2026 / Published: 4 July 2026

(This article belongs to the Special Issue Advancing Innovations in Biomedical Research for Translational Applications)

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Abstract

Sarcopenia is characterized by progressive loss of skeletal muscle mass and function and is a major contributor to frailty, disability, and mortality in older adults. Store-operated calcium entry (SOCE) is a crucial regulator of skeletal muscle calcium homeostasis, and impaired SOCE has been linked to age-related muscle weakness. Here, we identify the synaptophysin family member synaptophysin-like protein 2, also known as mitsugumin 29 (MG29; encoded by the human gene SYPL2 and the mouse ortholog Mg29), as a key organizer of triad membrane cholesterol and lipid signaling required for normal SOCE during aging. Using Mg29^−/− mice as a model of accelerated sarcopenia, together with RNA interference against Mg29 in adult muscle and primary myotubes, we quantified changes in muscle morphology, contractile function, SOCE activity, and targeted lipidomic profiles. Reduced MG29 expression led to decreased muscle fiber cross-sectional area, reduced specific force, blunted SOCE, and marked alterations in membrane cholesterol content and fatty acid-derived lipid mediators. Cholesterol depletion by methyl-β-cyclodextrin in wild-type myotubes produced SOCE defects similar to those observed in aged wild-type and young Mg29⁻/⁻ muscles, indicating that MG29-dependent maintenance of membrane cholesterol is required for normal SOCE. Acute Mg29 knockdown also altered myogenic differentiation, the expression of calcium-handling and stress-response genes, and the release and consumption of specific polyunsaturated fatty acid-derived lipid mediators. Together, these findings identify MG29 as a critical regulator of SOCE and lipid signaling in skeletal muscle and suggest that its age-related decline contributes to sarcopenia by disrupting triad membrane organization and excitation–contraction coupling.

Keywords: mitsugumin 29; MG29; sarcopenia; SOCE; calcium homeostasis; skeletal muscle; lipid signaling

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MDPI and ACS Style

Awad, K.; Huang, J.; Aziz, M.N.; Wang, Z.; Brotto, L.; Lee, K.E.; Kim, J.; Karthikraj, R.; Gushchina, L.V.; Weisleder, N.; et al. Reduced Synaptophysin-like 2 (MG29/SYPL2) Levels Mimic Age-Related Alterations in Skeletal Muscle Calcium Homeostasis and Lipid Signaling. Biomolecules 2026, 16, 988. https://doi.org/10.3390/biom16070988

AMA Style

Awad K, Huang J, Aziz MN, Wang Z, Brotto L, Lee KE, Kim J, Karthikraj R, Gushchina LV, Weisleder N, et al. Reduced Synaptophysin-like 2 (MG29/SYPL2) Levels Mimic Age-Related Alterations in Skeletal Muscle Calcium Homeostasis and Lipid Signaling. Biomolecules. 2026; 16(7):988. https://doi.org/10.3390/biom16070988

Chicago/Turabian Style

Awad, Kamal, Jian Huang, Marian N. Aziz, Zhiying Wang, Leticia Brotto, Kyung Eun Lee, Jongsoo Kim, Rajendiran Karthikraj, Liubov V. Gushchina, Noah Weisleder, and et al. 2026. "Reduced Synaptophysin-like 2 (MG29/SYPL2) Levels Mimic Age-Related Alterations in Skeletal Muscle Calcium Homeostasis and Lipid Signaling" Biomolecules 16, no. 7: 988. https://doi.org/10.3390/biom16070988

APA Style

Awad, K., Huang, J., Aziz, M. N., Wang, Z., Brotto, L., Lee, K. E., Kim, J., Karthikraj, R., Gushchina, L. V., Weisleder, N., & Brotto, M. (2026). Reduced Synaptophysin-like 2 (MG29/SYPL2) Levels Mimic Age-Related Alterations in Skeletal Muscle Calcium Homeostasis and Lipid Signaling. Biomolecules, 16(7), 988. https://doi.org/10.3390/biom16070988

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Reduced Synaptophysin-like 2 (MG29/SYPL2) Levels Mimic Age-Related Alterations in Skeletal Muscle Calcium Homeostasis and Lipid Signaling

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