bims-musmir 2025-08-24 papers

J Biomed Sci. 2025 Aug 19. 32(1): 77

Activation of mitophagy and proteasomal degradation confers resistance to developmental defects in postnatal skeletal muscle.

Fasih A Rahman, Mackenzie Q Graham, Alex Truong, Joe Quadrilatero.

BACKGROUND: Postnatal skeletal muscle development leads to increased muscle mass, strength, and mitochondrial function, but the role of mitochondrial remodeling during this period is unclear. This study investigates mitochondrial remodeling during postnatal muscle development and examines how constitutive autophagy deficiency impacts these processes.
METHODS: We initially performed a broad RNA-Seq analysis using a publicly available GEO database of skeletal muscle from postnatal day 7 (P7) to postnatal day 112 (P112) to identify differentially expressed genes. This was followed by investigation of postnatal skeletal muscle development using the mitophagy report mouse line (mt-Kiema mice), as well as conditional skeletal muscle knockout (Atg7f/f:Acta1-Cre) mice.
RESULTS: Our study observed rapid growth of body and skeletal muscle mass, along with increased fiber cross-sectional area and grip strength. Mitochondrial maturation was indicated by enhanced maximal respiration, reduced electron leak, and elevated mitophagic flux, as well as increased mitochondrial localization of autophagy and mitophagy proteins. Anabolic signaling was also upregulated, coinciding with increased mitophagy and fusion signaling, and decreased biogenesis signaling. Despite the loss of mitophagic flux in skeletal muscle-specific Atg7 knockout mice, there were no changes in body or skeletal muscle mass; however, hypertrophy was observed in type IIX fibers. This lack of Atg7 and loss of mitophagy was associated with the activation of mitochondrial apoptotic signaling as well as ubiquitin-proteasome signaling, suggesting a shift in degradation mechanisms. Inhibition of the ubiquitin-proteasome system (UPS) in autophagy-deficient skeletal muscle led to significant atrophy, increased reactive oxygen species production, and mitochondrial apoptotic signaling.
CONCLUSION: These results highlight the role of mitophagy in postnatal skeletal muscle development and suggest that autophagy-deficiency triggers compensatory degradative pathways (i.e., UPS) to prevent mitochondrial apoptotic signaling and thus preserve skeletal muscle integrity in developing mice.

Keywords: Apoptosis; Autophagy; BNIP3; Development; Mitochondria; Mitophagy; Skeletal muscle; UPS

DOI: https://doi.org/10.1186/s12929-025-01153-7

Redox Biol. 2025 Aug 14. pii: S2213-2317(25)00337-4. [Epub ahead of print]86 103824

Nuclear pore complex dysfunction drives TDP-43 pathology in ALS.

O Ramírez-Núñez, S Rico-Ríos, P Torres, V Ayala, A Fernàndez-Bernal, M Ceron-Codorniu, P Andrés-Benito, A Vinyals, S Maqsood, I Ferrer, R Pamplona, M Portero-Otin.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration and pathological aggregation of TDP-43. While protein misfolding and impaired autophagy are established features, accumulating evidence highlights the nuclear pore complex (NPC)as a vulnerable, redox-sensitive hub in ALS pathogenesis. Here, we show that selective loss of NPC components, particularly the scaffold proteins NUP107 and NUP93, and FG-repeat-containing components-is a consistent finding across ALS postmortem spinal cord, SOD1^G93A and TDP-43 mutant mouse models, and human cell systems.CRISPR-mediated depletion of NUP107 in human cells triggers hallmark features of ALS pathology, including cytoplasmic TDP-43 mislocalization, increased phosphorylation, and autophagy dysfunction. Conversely, TDP-43 knockdown perturbs NPC composition, suggesting a reciprocal regulatory loop. Crucially, we demonstrate that oxidative stress exacerbated NPC subunit mislocalization and enhanced TDP-43 aggregation. Using oxime blotting and DNPH assays, we show that FG-repeat subunits of NPC were direct targets of redox-driven carbonylation, indicating that oxidative modifications compromise NPC integrity thuspotentially affecting nucleocytoplasmic transport. Our findings established NPC dysfunction as a redox-sensitive driver of TDP-43 pathology in ALS and highlight nucleocytoplasmic transport as a promising therapeutic axis. The susceptibility of long-lived NPC proteins to oxidative damage provides a mechanistic link between redox stress, proteostasis collapse, and neurodegeneration.

DOI: https://doi.org/10.1016/j.redox.2025.103824

Genetics. 2025 Aug 19. pii: iyaf166. [Epub ahead of print]

The mitochondrial trans-2-enoyl-coA reductase is necessary for mitochondrial homeostasis in C. elegans.

Katherine Spilsbury, Jing Wu, Michael Reidy, Peter A Kropp.

Fatty acids function not only as signaling molecules and for energy storage, but also as essential cofactors for mitochondrial enzymes. These fatty acid cofactors are produced by the mitochondrial fatty acid synthesis pathway (mtFAS), the terminal enzyme of which is mitochondrial trans-2-enoyl-coA reductase (MECR). Dysfunction of MECR prevents the synthesis of fatty acids and is the monogenic cause of MEPAN syndrome, a rare mitochondrial disease characterized by dystonia, basal ganglia degeneration, and optic nerve atrophy. Given the necessity of mtFAS products for mitochondrial function, MECR should be essential. Yet, evidence from MEPAN individuals and model organisms with MECR loss of function indicate that mitochondrial function is not as severely impaired as would be expected. However, many of these studies have been limited to single cells or cell types. To better understand the role of MECR and its products in a multicellular system, we used CRISPR/Cas9 to knock out its two orthologs in C. elegans, MECR-1 and MECR-2. We found that only MECR-1 is necessary for normal mitochondrial function, germline development, and neuromuscular function. We thus establish a model in which further studies of MECR/MECR-1 can clarify its biochemical, developmental, and physiological roles.

Keywords: C. elegans ; MECR; Mitochondria; Mitochondrial trans-2-Enoyl-CoA Reductase; mtFAS

DOI: https://doi.org/10.1093/genetics/iyaf166

J Nutr Health Aging. 2025 Aug 16. pii: S1279-7707(25)00177-0. [Epub ahead of print]29(10): 100652

Weighing the risk of GLP-1 treatment in older adults: Should we be concerned about sarcopenic obesity?

Konstantinos Prokopidis, Robin M Daly, Charlotte Suetta.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been pivotal for obesity treatment, achieving 15-25 % weight loss over 12-24 months, but questions remain about the potential influence of concomitant losses in muscle mass. Furthermore, low adherence, driven by high costs and side effects, results in up to two-thirds of users discontinuing treatment within a year, although up to a half reinitiate treatment. Given that cessation of treatment often leads to significant weight regain, there are concerns that older adults may be at risk for sarcopenic obesity; a condition characterized by excessive adiposity and low skeletal muscle mass which is prevalent in 10-20 % of older adults. The risk for sarcopenic obesity may be further exacerbated by weight cycling related to repeated treatment cessation which may concomitantly exacerbate fat mass gains while reducing muscle mass. This mini-review examines the risk of sarcopenic obesity as an unintended consequence of GLP-1 RA cessation in older adults, highlighting the need for raising awareness and preventative strategies.

Keywords: Ageing; GLP-1 receptor agonists; Sarcopenic obesity; Weight cycling; Weight loss

DOI: https://doi.org/10.1016/j.jnha.2025.100652