Skeletal muscle: a significant novel neurohypophyseal hormone-secreting organ

Vasopressin (arg8-vasopressin) and oxytocin are closely relalated hormones, synthesized as pre-hormones in the magnocellular neurons of the paraventricular Q6 and supraoptic nuclei of the hypothalamus. Vasopressin and oxytocin are secreted in response to a variety of physiological stimuli, serving such different functions as controlling water balance, milk ejection, uterine contraction, mood, and parental behavior (Lechan and Toni, 2000; Costa et al., 2014a)

Of faeces and sweat. How much a mouse is willing to run: having a hard time measuring spontaneous physical activity in different mouse sub-strains

Physical activity has multiple beneficial effects in the physiology and pathology of the organism. In particular, we and other groups have shown that running counteracts cancer cachexia in both humans and rodents. The latter are prone to exercise in wheel-equipped cages even at advanced stages of cachexia. However, when we wanted to replicate the experimental model routinely used at the University of Rome in a different laboratory (i.e. at Paris 6 University), we had to struggle with puzzling results due to unpredicted mouse behavior. Here we report the experience and offer the explanation underlying these apparently irreproducible results. The original data are currently used for teaching purposes in undergraduate student classes of biological sciences

Regulation of skeletal muscle development and homeostasis by gene imprinting, histone acetylation and microRNA

Epigenetics is defined as heritable information other that the DNA sequence itself. The concept implies that the regulation of gene expression is highly complex and epigenetics can control from fine tuning to permanent gene activation/deactivation. Skeletal muscle is the main tissue for locomotion and energy metabolism in the body, and represent at least 40% of the body mass. Body mass and function vary according to age but also quickly adapt to physiological as well as pathological cues. Besides transcriptional mechanisms that control muscle differentiation, postnatal growth and remodeling, there are numerous epigenetic mechanisms of regulation that modulate muscle gene expression. In this review, we describe and discuss only some of the mechanisms of epigenetic regulation - such as DNA methylation, histone modifications, and microRNAs - that have been characterized in detail and that we believe are crucial for skeletal muscle development and disease

Chemotherapy-induced muscle wasting: an update

The majority of cancers are associated to cachexia, a severe form of weight loss mostly accounted for by skeletal muscle wasting. Cancer patients are often treated with chemotherapy, whose side effects are at times neglected or underestimated. Paradoxically, chemotherapy itself can induce muscle wasting with severe, cancer-independent effects on muscle homeostasis. Since muscle wasting is a primary marker of poor prognosis for cancer patients and negatively affects their quality of life, the systemic consequences of chemotherapy in this context must be fully characterized and taken into account. Ten years ago a precursor study in an animal cancer model was published in the European Journal of Translation Myology (back then, Basic and Applied Myology), highlighting that the side effects of chemotherapy include muscle wasting, possibly mediated by NF-κB activation. This paper, entitled «Chemotherapy-induced muscle wasting: association with NF-κB and cancer cachexia», is now being reprinted for the inaugural issue of the «Ejtm Seminal Paper Series». In this short review we discuss those results in the light of the most recent advances in the study of chemotherapy-induced muscle wasting

Increasing autophagy does not affect neurogenic muscle atrophy

Physiological autophagy plays a crucial role in the regulation of muscle mass and metabolism, while the excessive induction or the inhibition of the autophagic flux contributes to the progression of several diseases. Autophagy can be activated by different stimuli, including cancer, exercise, caloric restriction and denervation. The latter leads to muscle atrophy through the activation of catabolic pathways, i.e. the ubiquitin-proteasome system and autophagy. However, the kinetics of autophagy activation and the upstream molecular pathways in denervated skeletal muscle have not been reported yet. In this study, we characterized the kinetics of autophagic induction, quickly triggered by denervation, and report the Akt/mTOR axis activation. Besides, with the aim to assess the relative contribution of autophagy in neurogenic muscle atrophy, we triggered autophagy with different stimuli along with denervation, and observed that four week-long autophagic induction, by either intermitted fasting or rapamycin treatment, did not significantly affect muscle mass loss. We conclude that: i) autophagy does not play a major role in inducing muscle loss following denervation; ii) nonetheless, autophagy may have a regulatory role in denervation induced muscle atrophy, since it is significantly upregulated as early as eight hours after denervation; iii) Akt/mTOR axis, AMPK and FoxO3a are activated consistently with the progression of muscle atrophy, further highlighting the complexity of the signaling response to the atrophying stimulus deriving from denervation

MYOGENIC DIFFERENTIATION AND MUSCLE HOMEOSTASIS: NOVEL ROLES OF VASOPRESSIN

The neurohypophyseal nonapeptide arg-vasopressin (AVP) and related peptides constitute a novel family of positive regulators of terminal differentiation of myogenic cell lines and primary satellite cells. By interacting with V1 type receptor, AVP induces activation of phospholipases C and D, regulates cAMP levels, increases cytosolic Ca2+ concentration and up-regulates Myf-5 and myogenin expression, both at the mRNA and at the protein level. In a chemically defined medium, which eliminates the interference of serum components, AVP activates both the calcineurin and the CaMK signaling pathways, whose combined activation leads to the formation of multifactor complexes and is required for the full expression of the differentiated phenotype in vitro. To better clarify the physiological role of AVP in skeletal muscle, we analyzed the AVP effects on muscle regeneration induced by cardiotoxin injection. In particular, to increase skeletal muscle sensibility to circulating AVP, in the absence of systemic effects related to administration of the hormone itself, we over-expressed the V1a AVP receptor in mouse tibialis anterior muscle by electroporation-mediated gene delivery in vivo. The local over-expression of the V1aR in injured muscle results in enhanced regeneration. V1aR over-expressing muscle exhibits: early activation of satellite cells and regeneration markers, accelerated differentiation, increased cell population expressing hematopoietic stem cell markers and its conversion to the myogenic lineage. We demonstrate that V1aR over-expressing muscle increases calcineurin and IL-4 expression levels, and induces the phosphorylation of FOXO trascription factors, inhibiting the expression of atrophic genes. This study highlights a novel in vivo role for the AVP-dependent pathways which may represent a potential gene therapy approach for many diseases affecting muscle homeostasis

Spontaneous physical activity down-regulates Pax7 in cancer cachexia

Emerging evidence suggests that the muscle microenvironment plays a prominent role in cancer cachexia. We recently showed that NF-kB - induced Pax7 overexpression impairs the myogenic potential of muscle precursors in cachectic mice, suggesting that lowering Pax7 expression may be beneficial in cancer cachexia. We evaluated the muscle regenerative potential after acute injury in C26 colon carcinoma tumor-bearing mice and healthy controls. Our analyses confirmed that the delayed muscle regeneration observed in muscles form tumor-bearing mice was associated with a persistent local inflammation and Pax7 overexpression. Physical activity is known to exert positive effects on cachectic muscles. However, the mechanism by which a moderate voluntary exercise ameliorates muscle wasting is not fully elucidated. To verify if physical activity affects Pax7 expression, we hosted control and C26-bearing mice in wheel-equipped cages and we found that voluntary wheel running down-regulated Pax7 expression in muscles from tumor-bearing mice. As expected, down-regulation of Pax7 expression was associated with a rescue of muscle mass and fiber size. Our findings shed light on the molecular basis of the beneficial effect exerted by a moderate physical exercise on muscle stem cells in cancer cachexia. Furthermore, we propose voluntary exercise as a physiological tool to counteract the over-expression of Pax7observed in cancer cachexia

Stretching graphene using polymeric micro-muscles

The control of strain in two-dimensional materials opens exciting perspectives for the engineering of their electronic properties. While this expectation has been validated by artificial-lattice studies, it remains elusive in the case of atomic lattices. Remarkable results were obtained on nanobubbles and nano-wrinkles, or using scanning probes; microscale strain devices were implemented exploiting deformable substrates or external loads. These devices lack, however, the flexibility required to fully control and investigate arbitrary strain profiles. Here, we demonstrate a novel approach making it possible to induce strain in graphene using polymeric micrometric artificial muscles (MAMs) that contract in a controllable and reversible way under an electronic stimulus. Our method exploits the mechanical response of poly-methyl-methacrylate (PMMA) to electron-beam irradiation. Inhomogeneous anisotropic strain and out-of-plane deformation are demonstrated and studied by Raman, scanning-electron and atomic-force microscopy. These can all be easily combined with the present device architecture. The flexibility of the present method opens new opportunities for the investigation of strain and nanomechanics in two-dimensional materials

Mesenchymal Stem Cells as Promoters, Enhancers, and Playmakers of the Translational Regenerative Medicine.

Since their first isolation and characterization by Friedenstein et al. in 1974 [1], mesenchymal stem cells (MSCs) were proven essential for tissue regeneration and homeostasis

The mechanical stimulation of myotubes counteracts the effects of tumor-derived factors through the modulation of the activin/follistatin ratio

Activin negatively affects muscle fibers and progenitor cells in aging (sarcopenia) and in chronic diseases characterized by severe muscle wasting (cachexia). High circulating activin levels predict poor survival in cancer patients. However, the relative impact of activin in mediating muscle atrophy and hampered homeostasis is still unknown. To directly assess the involvement of activin, and its physiological inhibitor follistatin, in cancer-induced muscle atrophy, we cultured C2C12 myotubes in the absence or in the presence of a mechanical stretching stimulus and in the absence or presence of C26 tumor-derived factors (CM), so as to mimic the mechanical stimulation of exercise and cancer cachexia, respectively. We found that CM induces activin release by myotubes, further exacerbating the negative effects of tumor-derived factors. In addition, mechanical stimulation is sufficient to counteract the adverse tumor-induced effects on muscle cells, in association with an increased follistatin/activin ratio in the cell culture medium, indicating that myotubes actively release follistatin upon stretching. Recombinant follistatin counteracts tumor effects on myotubes exclusively by rescuing fusion index, suggesting that it is only partially responsible for the stretch-mediated rescue. Therefore, besides activin, other tumor-derived factors may play a significant role in mediating muscle atrophy. In addition to increasing follistatin secretion mechanical stimulation induces additional beneficial responses in myotubes. We propose that in animal models of cancer cachexia and in cancer patients purely mechanical stimuli play an important role in mediating the rescue of the muscle homeostasis reported upon exercise