bims-musmir 2026-09-20 papers

Arthritis Rheumatol. 2026 Sep 17.

Transcriptomic Profiling in Skeletal Muscle Identifies Associations With Knee Osteoarthritis: the Study of Muscle, Mobility and Aging (SOMMA).

Daniel S Evans, Tyler A Mansfield, Gina M Many, Tyler J Sagendorf, Samaneh Farsijani, Bret H Goodpaster, Lauren M Sparks, Nancy E Lane.

OBJECTIVES: The association between skeletal muscle gene expression and knee osteoarthritis (OA) was examined among older adult participants of the Study of Muscle, Mobility and Aging (SOMMA).
METHODS: Inclusion criteria included knee radiographs and bulk RNA sequencing (RNAseq) in vastus lateralis muscle, resulting in 523 participants (56% female). Radiographic knee OA was determined by Kellgren-Lawrence (KL) grades. Differential gene expression was analyzed using a control group (KL ≤ 1, n = 326) and two nested case groups: (a) KL ≥ 2 (n = 197), (b) KL ≥ 3 (n = 112).
RESULTS: Compared with controls, there were 27 and 41 genes associated (FDR ≤ 0.05) with KL ≥ 2 and KL ≥ 3, respectively, and 16 genes significantly associated in both contrasts. For 15 of the 16 genes, the association magnitude was larger with more severe OA (KL ≥ 3). Genes associated in both contrasts included brain-derived neurotrophic factor (BDNF) and interferon regulatory factor-2 (IRF2). Gene sets enriched in KL ≥ 2 and KL ≥ 3 contrasts included DNA repair and branched chain amino acid (BCAA) catabolism.
CONCLUSIONS: Our results in older adult SOMMA participants indicate that knee OA is associated with genes and pathways expressed in skeletal muscle that are involved in pain sensitization, BCAA catabolism, muscle function preservation, calcium transport and storage, inflammation, and extracellular matrix remodeling. Additional longitudinal studies will be needed to determine how these genes could affect the progression of knee OA.

DOI: https://doi.org/10.1002/art.70341

Cell Rep. 2026 Sep 11. pii: S2211-1247(26)01057-0. [Epub ahead of print]45(9): 117979

mtDNA alterations in muscle progenitors determine myoblast differentiation and disrupt skeletal muscle architecture.

Ayesha Sen, Olivier R Baris, Yulia Schaumkessel, Sebastian Kallabis, Claudie Gabillard-Lefort, Valerie Desquiret, Rudolf J Wiesner, David Pla-Martín.

Mitochondrial DNA (mtDNA) damage has been linked to age-related tissue decline, yet its impact on muscle stem cells (MuSCs) integrity remains unclear. Here, we used a dominant-negative variant of the mitochondrial helicase Twinkle (p.K320E) to induce mtDNA instability in C2C12 and MuSCs, and examined myogenic differentiation. In C2C12, mtDNA alterations impaired respiratory complex assembly, increased reactive oxygen species, and disrupted differentiation. Proteomic analyses of differentiated C2C12 revealed extensive remodeling of the mitochondrial proteome. In vivo, during muscle regeneration, MuSCs expressing K320E generated fibers showing mitochondrial dysfunction and elevated oxidative stress. Furthermore, when mtDNA instability was induced during early postnatal stages, mtDNA alterations were progressively transmitted to mature myofibers, resulting in persistent fiber remodeling of the skeletal muscle. Together, these findings identify mtDNA instability in muscle progenitors as a driver of skeletal muscle remodeling and reveal that even modest levels of mtDNA alterations are sufficient to compromise skeletal muscle function.

Keywords: CP: developmental biology; mitochondria; mtDNA; muscle differentiation; satellite cells; skeletal muscle

DOI: https://doi.org/10.1016/j.celrep.2026.117979

Nat Commun. 2026 09 16. pii: 9647. [Epub ahead of print]17(1):

Cholesterol maintains the degradative capacity of lysosomes during clearance and recycling of dysfunctional mitochondria.

Haoning Yang, Koji Matsuhisa, Meng Wei, Wataru Nishi, Dylan Hong Zheng Koh, Aik Yong Sim, Isabelle Bonne, Yasunori Saheki.

Efficient clearance and recycling of dysfunctional mitochondria through the robust catabolic activity of lysosomes are essential for cellular health. However, how membrane lipids contribute to maintaining the degradative capacity of lysosomes remains poorly understood. Here, we show that cholesterol plays a critical role in preserving the functional integrity of degradative lysosomes. Clearance of damaged mitochondria by degradative lysosomes is tightly coupled with the acute accumulation of phosphatidylinositol 4-phosphate (PI4P) on the lysosomal surface via PI4KIIα activity. This PI4P accumulation activates oxysterol-binding protein (OSBP)-mediated cholesterol transport from the endoplasmic reticulum (ER) to lysosomal membranes. The resulting efflux of cholesterol from the ER activates sterol regulatory element-binding protein 2 (SREBP-2), enhancing cholesterol production. Sustained cholesterol accumulation on lysosomal membranes maintains lysosomal acidity and membrane integrity for efficient mitochondrial degradation. This degradation process then leads to the release of free fatty acids and their recycling and storage through the formation of DGAT1-dependent lipid droplets. These findings uncover a key phosphoinositide-regulated cholesterol transport pathway that promotes the clearance and recycling of dysfunctional mitochondria, a process whose impairment is closely linked to neurodegeneration.

DOI: https://doi.org/10.1038/s41467-026-77423-1

G3 (Bethesda). 2026 Sep 16. pii: jkag245. [Epub ahead of print]

Analysis of proteasome stress in different cell types defines a conserved transcriptional response signature and its modulation with aging.

Mamta Rai, Yong-Dong Wang, Anna Stephan, Anjana Nityanandam, Fabio Demontis.

The proteasome is essential for proteostasis. Transcriptional induction of proteasomal components occurs when the proteasome is inhibited, but an overview of the transcriptional responses caused by proteasome perturbation is missing. Here, we profiled transcriptional changes caused by chemical and genetic proteasome inhibition and defined time-dose responses in cells and organoids. Induction of proteasome components varied by cell type and inhibition mode, whereas other responses were consistent, including upregulation of chaperones and secreted factors, and repression of cell cycle regulators. A proteasome stress response signature was defined based on the genes consistently modulated across systems, and applying this signature to aging datasets revealed activation of this stress response in some tissues, including skeletal muscle. Moreover, secreted factors within the signature showed similar age-related changes in human plasma, suggesting systemic activation of this stress response with aging. Together, these findings define a transcriptional signature for monitoring proteasome stress during aging and age-related diseases.

Keywords: aging; organoids; proteasome; proteostasis; stress response; stress signature

DOI: https://doi.org/10.1093/g3journal/jkag245

Proc Natl Acad Sci U S A. 2026 Sep 22. 123(38): e2616684123

Lipids regulate export of lysosomal enzymes from the endoplasmic reticulum.

Baolong Xia, Myeonghoon Han, Isaac Park, Norbert Perrimon.

Lysosomal enzymes are synthesized in the Endoplasmic Reticulum (ER) and transported to lysosomes to execute their functions. Deficiencies in lysosomal enzymes or components of the lysosomal transport machinery result in lysosomal storage disorders. While mannose-6-phosphate mediated lysosomal enzymes sorting in the Golgi has been extensively characterized, the mechanisms governing their export from the ER remain elusive. Here, we show that de novo lipogenesis, a metabolic pathway responsible for fatty acid synthesis, regulates lysosomal enzyme transport. Inhibition of de novo lipogenesis leads to the retention of lysosomal enzymes within the ER. Mechanistically, fatty acid derived from de novo lipogenesis is used for Arf1 myristoylation. Myristoylated Arf1 promotes retrograde vesicle trafficking from the Golgi to the ER, thereby maintaining the homeostatic bidirectional flux required for efficient ER export of lysosomal enzymes. Our findings uncover a critical functional link between lipid metabolism and lysosomal enzyme trafficking.

Keywords: SREBP; de novo lipogenesis; lysosomal enzyme transport; protein myristoylation; proximity labeling

DOI: https://doi.org/10.1073/pnas.2616684123