bims-musmir 2025-01-05 papers

Nat Commun. 2025 Jan 02. 16(1): 80

Reduced ATP turnover during hibernation in relaxed skeletal muscle.

Cosimo De Napoli, Luisa Schmidt, Mauro Montesel, Laura Cussonneau, Samuele Sanniti, Lorenzo Marcucci, Elena Germinario, Jonas Kindberg, Alina Lynn Evans, Guillemette Gauquelin-Koch, Marco Narici, Fabrice Bertile, Etienne Lefai, Marcus Krüger, Leonardo Nogara, Bert Blaauw.

Hibernating brown bears, due to a drastic reduction in metabolic rate, show only moderate muscle wasting. Here, we evaluate if ATPase activity of resting skeletal muscle myosin can contribute to this energy sparing. By analyzing single muscle fibers taken from the same bears, either during hibernation or in summer, we find that fibers from hibernating bears have a mild decline in force production and a significant reduction in ATPase activity. Single fiber proteomics, western blotting, and immunohistochemical analyses reveal major remodeling of the mitochondrial proteome during hibernation. Furthermore, using bioinformatical approaches and western blotting we find that phosphorylated myosin light chain, a known stimulator of basal myosin ATPase activity, is decreased in hibernating and disused muscles. These results suggest that skeletal muscle limits energy loss by reducing myosin ATPase activity, indicating a possible role for myosin ATPase activity modulation in multiple muscle wasting conditions.

DOI: https://doi.org/10.1038/s41467-024-55565-4

Nat Commun. 2024 Dec 30. 15(1): 10786

Higher skeletal muscle mitochondrial oxidative capacity is associated with preserved brain structure up to over a decade.

Qu Tian, Erin E Greig, Christos Davatzikos, Bennett A Landman, Susan M Resnick, Luigi Ferrucci.

Impaired muscle mitochondrial oxidative capacity is associated with future cognitive impairment, and higher levels of PET and blood biomarkers of Alzheimer's disease and neurodegeneration. Here, we examine its associations with up to over a decade-long changes in brain atrophy and microstructure. Higher in vivo skeletal muscle oxidative capacity via MR spectroscopy (post-exercise recovery rate, kPCr) is associated with less ventricular enlargement and brain aging progression, and less atrophy in specific regions, notably primary sensorimotor cortex, temporal white and gray matter, thalamus, occipital areas, cingulate cortex, and cerebellum white matter. Higher kPCr is also associated with less microstructural integrity decline in white matter around cingulate, including superior longitudinal fasciculus, corpus callosum, and cingulum. Higher in vivo muscle oxidative capacity is associated with preserved brain structure up to over a decade, particularly in areas important for cognition, motor function, and sensorimotor integration.

DOI: https://doi.org/10.1038/s41467-024-55009-z

Life Sci. 2024 Dec 29. pii: S0024-3205(24)00933-0. [Epub ahead of print] 123343

Altering phosphorylation of dystrophin S3059 to attenuate cancer cachexia.

Kristy Swiderski, Jennifer Trieu, Annabel Chee, Timur Naim, Christopher J Brock, Dale M Baum, Audrey S Chan, Justin P Hardee, Wenlan Li, Andrew J Kueh, Marco J Herold, Kate T Murphy, Paul Gregorevic, Gordon S Lynch.

AIMS: Cancer cachexia affects up to 80 % of patients with advanced cancer and accounts for >20 % of all cancer-related deaths. Sarcolemmal localization of dystrophin, a key protein within the dystrophin-glycoprotein complex (DGC), is perturbed in multiple muscle wasting conditions, including cancer cachexia, indicating a potential role for dystrophin in the maintenance of muscle mass. Strategies to preserve dystrophin expression at the sarcolemma might therefore combat muscle wasting. Phosphorylation of dystrophin serine 3059 (S3059) enhances the interaction between dystrophin and β-dystroglycan and attenuates atrophy of mouse muscle myotubes in vitro when cultured in the presence of colon-26 (C-26) cancer cells. Whether dystrophin S3059 phosphorylation can attenuate cachexia in tumor-bearing mice has not been determined.
MATERIALS AND METHODS: Mice with systemic mutations of serine 3059 to alanine (DmdS3059A; phospho-null) or glutamate (DmdS3059E; phosphomimetic) were generated to investigate the impact of S3059 phosphorylation on survival and skeletal muscle health in the C-26 tumor-bearing mouse model of cancer cachexia using measures of skeletal muscle function in situ combined with biochemical and histological assessments.
KEY FINDINGS: In a model of mild cachexia, loss of skeletal muscle mass and function was greater in DmdS3059A mice. Conversely, in a model of severe cachexia, overall survival was prolonged, and markers of protein degradation were decreased in skeletal muscles of DmdS3059E mice. Thus, manipulating dystrophin S3059 phosphorylation can alter the progression of cachexia in tumor-bearing mice.
SIGNIFICANCE: Strategies to increase phosphorylation of this site, and/or increase dystrophin protein expression, have therapeutic potential for cancer cachexia.

Keywords: Cancer cachexia; Dystrophin; Dystrophin-glycoprotein complex; Mouse; Phosphorylation; S3059; Skeletal muscle

DOI: https://doi.org/10.1016/j.lfs.2024.123343

Nat Rev Neurol. 2025 Jan 02.

Targeting common disease pathomechanisms to treat amyotrophic lateral sclerosis.

Kiterie M E Faller, Helena Chaytow, Thomas H Gillingwater.

The motor neuron disease amyotrophic lateral sclerosis (ALS) is a devastating condition with limited treatment options. The past few years have witnessed a ramping up of translational ALS research, offering the prospect of disease-modifying therapies. Although breakthroughs using gene-targeted approaches have shown potential to treat patients with specific disease-causing mutations, the applicability of such therapies remains restricted to a minority of individuals. Therapies targeting more general mechanisms that underlie motor neuron pathology in ALS are therefore of considerable interest. ALS pathology is associated with disruption to a complex array of key cellular pathways, including RNA processing, proteostasis, metabolism and inflammation. This Review details attempts to restore cellular homeostasis by targeting these pathways in order to develop effective, broadly-applicable ALS therapeutics.

DOI: https://doi.org/10.1038/s41582-024-01049-4

Drug Discov Today. 2024 Dec 28. pii: S1359-6446(24)00408-2. [Epub ahead of print] 104283

Repairing muscle with broccoli-derived sulforaphane: A preclinical evaluation for the treatment of mitochondrial myopathies.

Thomas Lilley, Donny M Camera, Faith A A Kwa.

Skeletal muscle health relies on the production of adenosine triphosphate (ATP) in the mitochondria. ATP production is accompanied by oxidative phosphorylation, which generates reactive oxygen species (ROS). When there is an imbalance in ROS levels, oxidative stress and subsequent mitochondrial dysfunction, mitochondrial myopathies including sarcopenia, chronic progressive external ophthalmoplegia, and proximal myopathy can result. Such incurable myopathies are characterised by aberrant metabolism, limited ATP production, and muscle atrophy. Broccoli-derived sulforaphane has emerged as a novel treatment for mitochondrial myopathies because of its antioxidant and anti-inflammatory properties. This review discusses preclinical models that reveal sulforaphane's potential therapeutic benefits and limitations in treating mitochondrial myopathies.

Keywords: chronic progressive external ophthalmoplegia; inflammation; oxidative stress; proximal myopathy; sarcopenia; sulforaphane

DOI: https://doi.org/10.1016/j.drudis.2024.104283