Sunitinib-mediated inhibition of STAT3 in skeletal muscle and spinal cord does not affect the disease in a mouse model of ALS.

Variability in disease onset and progression is a hallmark of amyotrophic lateral sclerosis (ALS), both in sporadic and genetic forms. Recently, we found that SOD1-G93A transgenic mice expressing the same amount of mutant SOD1 but with different genetic backgrounds, C57BL/6JOlaHsd and 129S2/SvHsd, show slow and rapid muscle wasting and disease progression, respectively. Here, we investigated the different molecular mechanisms underlying muscle atrophy.

Integrated procedures for accelerating, deepening, and leading genetic inquiry: A first application on human muscle secretome.

Purpose: Beyond classical procedures, bioinformatic-assisted approaches and computational biology offer unprecedented opportunities for scholars. However, these amazing possibilities still need epistemological criticism, as well as standardized procedures. Especially those topics with a huge body of data may benefit from data science (DS)-assisted methods.

Will there be large or small gifts to PDM3 attendees and EJTM authors in March and June 2023?

The fall of 2022 approaches with the need to finalize our plans for next year. This is urgent for the 2023 Meeting of the Padua Days of Muscle and Mobility Medicine, (PDM3) to be held March 29 to April 1, 2023 at the Hotel Petrarca in the Thermae of Euganean Hills (Padua), Italy, but there are also news related to the inclusion of the European Journal of Translational Myology (EJTM) in the Web of Science: Emerging Sources Citation Index - Clarivate (ESCI) database. A preliminary PDM3 flyer is almost ready with session program, organzers and keynote speakers.

Transforming Growth Factor-Beta Signaling in Cancer-Induced Cachexia: From Molecular Pathways to the Clinics.

Cachexia is a metabolic syndrome consisting of massive loss of muscle mass and function that has a severe impact on the quality of life and survival of cancer patients. Up to 20% of lung cancer patients and up to 80% of pancreatic cancer patients are diagnosed with cachexia, leading to death in 20% of them. The main drivers of cachexia are cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), macrophage inhibitory cytokine 1 (MIC-1/GDF15) and transforming growth factor-beta (TGF-β).

The p97-Nploc4 ATPase complex plays a role in muscle atrophy during cancer and amyotrophic lateral sclerosis.

Background: The p97 complex participates in the degradation of muscle proteins during atrophy upon fasting or denervation interacting with different protein adaptors. We investigated whether and how it might also be involved in muscle wasting in cancer, where loss of appetite occurs, or amyotrophic lateral sclerosis (ALS), where motoneuron death causes muscle denervation and fatal paralysis.

Methods: As cancer cachexia models, we used mice bearing colon adenocarcinoma C26, human renal carcinoma RXF393, or Lewis lung carcinoma, with breast cancer 4T1-injected mice as controls.

Apelin Resistance Contributes to Muscle Loss during Cancer Cachexia in Mice.

Cancer cachexia consists of dramatic body weight loss with rapid muscle depletion due to imbalanced protein homeostasis. We found that the mRNA levels of apelin decrease in muscles from cachectic hepatoma-bearing rats and three mouse models of cachexia. Furthermore, expression inversely correlates with in muscle biopsies from cancer patients.

TRIM32: A Multifunctional Protein Involved in Muscle Homeostasis, Glucose Metabolism, and Tumorigenesis.

Human tripartite motif family of proteins 32 (TRIM32) is a ubiquitous multifunctional protein that has demonstrated roles in differentiation, muscle physiology and regeneration, and tumor suppression. Mutations in TRIM32 result in two clinically diverse diseases. A mutation in the B-box domain gives rise to Bardet-Biedl syndrome (BBS), a disease whose clinical presentation shares no muscle pathology, while mutations in the NHL (NCL-1, HT2A, LIN-41) repeats of TRIM32 causes limb-girdle muscular dystrophy type 2H (LGMD2H).

Costameric integrin and sarcoglycan protein levels are altered in a model for Limb-girdle muscular dystrophy type 2H.

Mutations in two different domains of the ubiquitously expressed TRIM32 protein give rise to two clinically separate diseases, one of which is Limb-girdle muscular dystrophy type 2H (LGMD2H). Uncovering the muscle-specific role of TRIM32 in LGMD2H pathogenesis has proven difficult, as neurogenic phenotypes, independent of LGMD2H pathology, are present in mice. We previously established a platform to study LGMD2H pathogenesis using as a model.

Nutraceuticals and Exercise against Muscle Wasting during Cancer Cachexia.

Cancer cachexia (CC) is a debilitating multifactorial syndrome, involving progressive deterioration and functional impairment of skeletal muscles. It affects about 80% of patients with advanced cancer and causes premature death. No causal therapy is available against CC.

Trabectedin and Lurbinectedin Extend Survival of Mice Bearing C26 Colon Adenocarcinoma, without Affecting Tumor Growth or Cachexia.

Trabectedin (ET743) and lurbinectedin (PM01183) limit the production of inflammatory cytokines that are elevated during cancer cachexia. Mice carrying C26 colon adenocarcinoma display cachexia (i.e.

Oxidation of HMGB1 Is a Dynamically Regulated Process in Physiological and Pathological Conditions.

Acute inflammation is a complex biological response of tissues to harmful stimuli, such as pathogens or cell damage, and is essential for immune defense and proper healing. However, unresolved inflammation can lead to chronic disorders, including cancer and fibrosis. The High Mobility Group Box 1 (HMGB1) protein is a Damage-Associated Molecular Pattern (DAMP) molecule that orchestrates key events in inflammation by switching among mutually exclusive redox states.

Musclin, A Myokine Induced by Aerobic Exercise, Retards Muscle Atrophy During Cancer Cachexia in Mice.

Physical activity improves the prognosis of cancer patients, partly by contrasting the associated muscle wasting (cachexia), through still unknown mechanisms. We asked whether aerobic exercise causes secretion by skeletal muscles of proteins (myokines) that may contrast cachexia. Media conditioned by peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α)-expressing myotubes, reproducing some metabolic adaptations of aerobic exercise, as increased mitochondrial biogenesis and oxidative phosphorylation, restrained constitutively active Forkhead box-containing subfamily O3 (caFoxO3)-induced proteolysis.

Exercise-Induced Myokines With Therapeutic Potential for Muscle Wasting.

Skeletal muscle is a highly vascularized tissue that can secrete proteins called myokines. These muscle-secreted factors exert biological functions in muscle itself (autocrine effect) or on short- or long-distant organs (paracrine/endocrine effects) and control processes such as metabolism, angiogenesis, or inflammation. Widely differing diseases ranging from genetic myopathies to cancers are emerging as causing dysregulated secretion of myokines from skeletal muscles.

Micro-computed tomography for non-invasive evaluation of muscle atrophy in mouse models of disease.

Muscle wasting occurs during various chronic diseases and precedes death in humans as in mice. The evaluation of the degree of muscle atrophy in diseased mouse models is often overlooked since it requires the sacrifice of the animals for muscle examination or expensive instrumentation and highly qualified personnel, such as Magnetic Resonance Imaging (MRI). Very often behavioral tests for muscle strength evaluation are used as an outcome measurement in preclinical therapeutic trials.

Group I Paks support muscle regeneration and counteract cancer-associated muscle atrophy.

Background: Skeletal muscle is characterized by an efficient regeneration potential that is often impaired during myopathies. Understanding the molecular players involved in muscle homeostasis and regeneration could help to find new therapies against muscle degenerative disorders. Previous studies revealed that the Ser/Thr kinase p21 protein-activated kinase 1 (Pak1) was specifically down-regulated in the atrophying gastrocnemius of Yoshida hepatoma-bearing rats.

Bioreducible Hydrophobin-Stabilized Supraparticles for Selective Intracellular Release.

One of the main hurdles in nanomedicine is the low stability of drug-nanocarrier complexes as well as the drug delivery efficiency in the region-of-interest. Here, we describe the use of the film-forming protein hydrophobin HFBII to organize dodecanethiol-protected gold nanoparticles (NPs) into well-defined supraparticles (SPs). The obtained SPs are exceptionally stable in vivo and efficiently encapsulate hydrophobic drug molecules.

The ubiquitin ligase tripartite-motif-protein 32 is induced in Duchenne muscular dystrophy.

Activation of the proteasome pathway is one of the secondary processes of cell damage, which ultimately lead to muscle degeneration and necrosis in Duchenne muscular dystrophy (DMD). In mdx mice, the proteasome inhibitor bortezomib up-regulates the membrane expression of members of the dystrophin complex and reduces the inflammatory reaction. However, chronic inhibition of the 26S proteasome may be toxic, as indicated by the systemic side-effects caused by this drug.

Sunitinib prevents cachexia and prolongs survival of mice bearing renal cancer by restraining STAT3 and MuRF-1 activation in muscle.

Tyrosine kinase inhibitors, affecting angiogenesis, have shown therapeutic efficacy in renal cell carcinoma (RCC). The increased overall survival is not fully explained by their anti-tumor activity, since these drugs frequently induce disease stabilization rather than regression. RCC patients frequently develop cachectic syndrome.

Mechanisms of skeletal muscle aging: insights from Drosophila and mammalian models.

A characteristic feature of aged humans and other mammals is the debilitating, progressive loss of skeletal muscle function and mass that is known as sarcopenia. Age-related muscle dysfunction occurs to an even greater extent during the relatively short lifespan of the fruit fly Drosophila melanogaster. Studies in model organisms indicate that sarcopenia is driven by a combination of muscle tissue extrinsic and intrinsic factors, and that it fundamentally differs from the rapid atrophy of muscles observed following disuse and fasting.

Mechanisms of muscle growth and atrophy in mammals and Drosophila.

Background: The loss of skeletal muscle mass (atrophy) that accompanies disuse and systemic diseases is highly debilitating. Although the pathogenesis of this condition has been primarily studied in mammals, Drosophila is emerging as an attractive system to investigate some of the mechanisms involved in muscle growth and atrophy.

Results: In this review, we highlight the outstanding unsolved questions that may benefit from a combination of studies in both flies and mammals.

Expression of OA1 limits the fusion of a subset of MVBs with lysosomes - a mechanism potentially involved in the initial biogenesis of melanosomes.

Multivesicular endosomes/bodies (MVBs) deliver proteins, such as activated EGF receptor (EGFR), to the lysosome for degradation, and, in pigmented cells, MVBs containing PMEL are an initial stage in melanosome biogenesis. The mechanisms regulating numbers and fate of different populations of MVB are unclear. Here, we focus on the role of the G-protein-coupled receptor OA1 (also known as GPR143), which is expressed exclusively in pigmented cells and mutations in which cause the most common type of ocular albinism.

The influence of skeletal muscle on systemic aging and lifespan.

Epidemiological studies in humans suggest that skeletal muscle aging is a risk factor for the development of several age-related diseases such as metabolic syndrome, cancer, Alzheimer's and Parkinson's disease. Here, we review recent studies in mammals and Drosophila highlighting how nutrient- and stress-sensing in skeletal muscle can influence lifespan and overall aging of the organism. In addition to exercise and indirect effects of muscle metabolism, growing evidence suggests that muscle-derived growth factors and cytokines, known as myokines, modulate systemic physiology.