Displaced Myonuclei in Cancer Cachexia Suggest Altered Innervation.

An idiopathic myopathy characterized by central nuclei in muscle fibers, a hallmark of muscle regeneration, has been observed in cancer patients. In cancer cachexia skeletal muscle is incapable of regeneration, consequently, this observation remains unaccounted for. In C26-tumor bearing, cachectic mice, we observed muscle fibers with central nuclei in the absence of molecular markers of bona fide regeneration. These clustered, non-peripheral nuclei were present in NCAM-expressing muscle fibers. Since NCAM expression is upregulated in denervated myofibers, we searched for additional makers of denervation, including AchRs, MUSK, and HDAC. This last one being also consistently upregulated in cachectic muscles, correlated with an increase of central myonuclei. This held true in the musculature of patients suffering from gastrointestinal cancer, where a progressive increase in the number of central myonuclei was observed in weight stable and in cachectic patients, compared to healthy subjects. Based on all of the above, the presence of central myonuclei in cancer patients and animal models of cachexia is consistent with motor neuron loss or NMJ perturbation and could underlie a previously neglected phenomenon of denervation, rather than representing myofiber damage and regeneration in cachexia. Similarly to aging, denervation-dependent myofiber atrophy could contribute to muscle wasting in cancer cachexia.

A new role for the calcineurin/NFAT pathway in neonatal myosin heavy chain expression via the NFATc2/MyoD complex during mouse myogenesis.

The calcineurin/NFAT (nuclear factor of activated T-cells) signaling pathway is involved in the modulation of the adult muscle fiber type, but its role in the establishment of the muscle phenotype remains elusive. Here, we show that the NFAT member NFATc2 cooperates with the basic helix-loop-helix transcription factor MyoD to induce the expression of a specific myosin heavy chain (MHC) isoform, the neonatal one, during embryogenesis. We found this cooperation to be crucial, as Myod/Nfatc2 double-null mice die at birth, with a dramatic reduction of the major neonatal MHC isoform normally expressed at birth in skeletal muscles, such as limb and intercostal muscles, whereas its expression is unaffected in myofibers mutated for either factor alone. Using gel shift and chromatin immunoprecipitation assays, we identified NFATc2 bound to the neonatal Mhc gene, whereas NFATc1 and NFATc3 would preferentially bind the embryonic Mhc gene. We provide evidence that MyoD synergistically cooperates with NFATc2 at the neonatal Mhc promoter. Altogether, our findings demonstrate that the calcineurin/NFAT pathway plays a new role in establishing the early muscle fiber type in immature myofibers during embryogenesis.

Srf KO and wild-type mice similarly adapt to endurance exercise.

Physical exercise has important effects as secondary prevention or intervention against several diseases. Endurance exercise induces local and global effects, resulting in skeletal muscle adaptations to aerobic activity and contributes to an amelioration of muscle performance. Furthermore, it prevents muscle loss. Serum response factor (Srf) is a transcription factor of pivotal importance for muscle tissues and animal models of Srf genetic deletion/over-expression are widely used to study Srf role in muscle homeostasis, physiology and pathology. A global characterisation of exercise adaptation in the absence of Srf has not been reported. We measured body composition, muscle force, running speed, energy expenditure and metabolism in WT and inducible skeletal muscle-specific Srf KO mice, following three weeks of voluntary exercise by wheel running. We found a major improvement in the aerobic capacity and muscle function in WT mice following exercise, as expected, and no major differences were observed in Srf KO mice as compared to WT mice, following exercise. Taken together, these observations suggest that Srf is not required for an early (within 3 weeks) adaptation to spontaneous exercise and that Srf KO mice behave similarly to the WT in terms of spontaneous physical activity and the resulting adaptive responses. Therefore, Srf KO mice can be used in functional muscle studies, without the results being affected by the lack of Srf. Since lack of Srf induces premature sarcopenia, our observations suggest that the modifications due to the absence of Srf take time to occur and that young, Srf KO mice behave similarly to WT in aerobic physical activities.

Serum Response Factor in Muscle Tissues: From Development to Ageing.

Skeletal, cardiac and smooth muscle cells share various common characteristic features. During development the embryonic mesodermal layer contribute at different proportions to the formation of these tissues. At the functional level, contractility as well as its decline during ageing, are also common features. Cytoskeletal components of these tissues are characterized by various actin isoforms that govern through their status (polymerised versus monomeric) and their interaction with the myosins the contractile properties of these muscles. Finally, at the molecular level, a set of different transcription factors with the notable exception of Serum Response Factor SRF- which is commonly enriched in the 3 types of muscle- drive and maintain the differentiation of these cells (Myf5, MyoD, Myogenin for skeletal muscle; Nkx2.5, GATA4 for cardiomyocytes). In this review, we will focus on the transcription factor SRF and its role in the homeostasis of cardiac, smooth and skeletal muscle tissues as well as its behaviour during the age related remodelling process of these tissues with a specific emphasis on animal models and human data when available.