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Department of Animal Sciences
The Robert H. Smith Faculty
of Agricultural, Food & Environment

The Hebrew University of Jerusalem.

P.O. Box 12, Rehovot 76100, Israel
Phone: +972-(0)8-9489119;
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Patael, T. ; Piestun, Y. ; Soffer, A. ; Mordechay, S. ; Yahav, S. ; Velleman, S. G. ; Halevy, O. Early posthatch thermal stress causes long-term adverse effects on pectoralis muscle development in broilers. Poultry Science 2019. Publisher's VersionAbstract
Broiler chicks in the immediate posthatch handling period are exposed to thermal stress, with potentially harmful consequences for muscle growth and structure (e.g., less protein and more fat deposition). We addressed the effects of broiler chicks' exposure to various ambient temperatures during the first 13 D posthatch on their performance, as well as on muscle development and structure, up to day 35. Body weight and pectoralis muscle growth were lower throughout the entire period in the high-heat-exposed chicks (39°C, Hot) and to a lesser extent in the mild-heat-exposed chicks (35°C, Hot Mild) than in the Control chicks that were raised under a commercial protocol. In the cold-exposed chicks (29oC, Cold), BW and pectoralis muscle absolute growth were similar to the Control group throughout the entire period. The lower body and muscle growth in the Hot and Hot Mild groups were reflected in a lower number of myonuclei expressing proliferating cell nuclear cell in pectoralis major muscle cross sections sampled on day 8, in the distribution of myofibers as the experiment progressed, and in mean myofiber diameter on day 35, whereas in the Cold group, these numbers exceeded that of the Control group. However, TUNEL assay revealed similar cell survival in all groups. Hematoxylin–eosin and Oil red O staining revealed the highest fat deposition in the pectoralis muscle derived from the Hot group, whereas lower fat deposition was observed in the Control Cold group. These results were corroborated by immunostaining for CCAAT/enhancer binding protein β in the pectoralis muscle, the levels of which were significantly higher in the Hot and Hot Mild groups on day 35 than in the Control group. Similar results were observed with Sirius red staining for collagen content in the pectoralis muscle. Together, the results imply long-term effects of chronic heat stress vs. cold stress in the early posthatch period on the broiler's body and muscle growth in general and myodegeneration of the pectoralis muscle in particular.
Wellner, G. ; Mordechay, S. ; Evans, P. ; Genin, O. ; Pines, M. ; Halevy, O. Hydroxy group requirement for halofuginone-dependent inhibition of muscle fibrosis and improvement of histopathology in the mdx mouse model for Duchenne muscular dystrophy. Histol Histopathol. 2019, 34, 791 - 801. Publisher's Version
Barzilai-Tutsch, H. ; Dewulf, M. ; Lamaze, C. ; Butler Browne, G. ; Pines, M. ; Halevy, O. A promotive effect for halofuginone on membrane repair and synaptotagmin-7 levels in muscle cells of dysferlin-null mice. Hum Mol Genet 2018, 27, 2817-2829.Abstract
In the absence of dysferlin, skeletal muscle cells fail to reseal properly after injury, resulting in slow progress of the dysferlinopathy muscular dystrophy (MD). Halofuginone, a leading agent in preventing fibrosis in MDs, was tested for its effects on membrane resealing post-injury. A hypo-osmotic shock assay on myotubes derived from wild-type (Wt) and dysferlin-null (dysf-/-) mice revealed that pre-treatment with halofuginone reduces the percentage of membrane-ruptured myotubes only in dysf-/- myotubes. In laser-induced injury of isolated myofibers, halofuginone decreased the amount of FM1-43 at the injury site of dysf-/- myofibers while having no effect on Wt myofibers. These results implicate halofuginone in ameliorating muscle-cell membrane integrity in dysf-/- mice. Halofuginone increased lysosome scattering across the cytosol of dysf-/- primary myoblasts, in a protein kinase/extracellular signal-regulated protein kinase and phosphoinositide 3 kinase/Akt-dependent manner, in agreement with an elevation in lysosomal exocytotic activity in these cells. A spatial- and age-dependent synaptotagmin-7 (Syt-7) expression pattern was shown in dysf-/- versus Wt mice, suggesting that these pattern alterations are related to the disease progress and that sytnaptotagmin-7 may be compensating for the lack of dysferlin at least with regard to membrane resealing post-injury. While halofuginone did not affect patch-repair-complex key proteins, it further enhanced Syt-7 levels and its spread across the cytosol in dysf-/- myofibers and muscle tissue, and increased its co-localization with lysosomes. Together, the data imply a novel role for halofuginone in membrane-resealing events with Syt-7 possibly taking part in these events.
Pines, M. ; Levi, O. ; Genin, O. ; Lavy, A. ; Angelini, C. ; Allamand, V. ; Halevy, O. Elevated Expression of Moesin in Muscular Dystrophies. The American Journal of Pathology 2017, 187, 654 - 664. Publisher's VersionAbstract
Fibrosis is the main complication of muscular dystrophies. We identified moesin, a member of the ezrin-radixin-moesin family, in dystrophic muscles of mice representing Duchenne and congenital muscular dystrophies (DMD and CMD, respectively) and dysferlinopathy, but not in the wild type. High levels of moesin were also observed in muscle biopsy specimens from DMD, Ullrich CMD, and merosin-deficient CMD patients, all of which present high levels of fibrosis. The myofibroblasts, responsible for extracellular matrix protein synthesis, and the macrophages infiltrating the dystrophic muscles were the source of moesin. Moesin-positive cells were embedded within the fibrotic areas between the myofibers adjacent to the collagen type I fibers. Radixin was also synthesized by the myofibroblasts, whereas ezrin colocalized with the myofiber membranes. In animal models and patients' muscles, part of the moesin was in its active phosphorylated form. Inhibition of fibrosis by halofuginone, an antifibrotic agent, resulted in a major decrease in moesin levels in the muscles of DMD and CMD mice. In summary, the results of this study may pave the way for exploiting moesin as a novel target for intervention in MDs, and as part of a battery of biomarkers to evaluate treatment success in preclinical studies and clinical trials.
Piestun, Y. ; Patael, T. ; Yahav, S. ; Velleman, S. G. ; Halevy, O. Early posthatch thermal stress affects breast muscle development and satellite cell growth and characteristics in broilers. Poultry Science 2017, 96, 2877 - 2888. Publisher's VersionAbstract
ABSTRACT Heat or cold stress, can disrupt well-being and physiological responses in birds. This study aimed to elucidate the effects of continuous heat exposure in the first 2 wk of age on muscle development in broilers, with an emphasis on the pectoralis muscle satellite cell population. Chicks were reared for 13 d under either commercial conditions or a temperature regime that was 5°C higher. Body and muscle weights, as well as absolute muscle growth were lower in heat-exposed chicks from d 6 onward. The number of satellite cells derived from the experimental chicks was higher in the heat-treated group on d 3 but lower on d 8 and 13 compared to controls. This was reflected in a lower number of myonuclei expressing proliferating nuclear cell antigen in cross sections of pectoralis major muscle sampled on d 8. However, a TUNEL assay revealed similar cell survival in both groups. Mean myofiber diameter and distribution were lower in muscle sections sampled on d 8 and 13 in heat-treated versus control group, suggesting that the lower muscle growth is due to changes in muscle hypertrophy. Oil-Red O staining showed a higher number of satellite cells with lipids in the heat-treated compared to the control group on these days. Moreover, lipid deposition was observed in pectoralis muscle cross sections derived from the heat-treated chicks on d 13, whereas the controls barely exhibited any lipid staining. The gene and protein expression levels of CCAAT/enhancer binding protein β in pectoralis muscle from the heat-treated group were significantly higher on d 13 than in controls, while myogenin levels were similar. The results suggest high sensitivity of muscle progenitor cells in the early posthatch period at a time when they are highly active, to chronic heat exposure, leading to impaired myogenicity of the satellite cells and increased fat deposition.
Barzilai-Tutsch, H. ; Bodanovsky, A. ; Maimon, H. ; Pines, M. ; Halevy, O. Halofuginone promotes satellite cell activation and survival in muscular dystrophies. 2016, 1862, 1 - 11. Publisher's VersionAbstract
Halofuginone is a leading agent in preventing fibrosis and inflammation in various muscular dystrophies. We hypothesized that in addition to these actions, halofuginone directly promotes the cell-cycle events of satellite cells in the mdx and dysf−/− mouse models of early-onset Duchenne muscular dystrophy and late-onset dysferlinopathy, respectively. In both models, addition of halofuginone to freshly prepared single gastrocnemius myofibers derived from 6-week-old mice increased BrdU incorporation at as early as 18h of incubation, as well as phospho-histone H3 (PHH3) and MyoD protein expression in the attached satellite cells, while having no apparent effect on myofibers derived from wild-type mice. BrdU incorporation was abolished by an inhibitor of mitogen-activated protein kinase/extracellular signal-regulated protein kinase, suggesting involvement of this pathway in mediating halofuginone's effects on cell-cycle events. In cultures of myofibers and myoblasts isolated from dysf−/− mice, halofuginone reduced Bax and induced Bcl2 expression levels and induced Akt phosphorylation in a time-dependent manner. Addition of an inhibitor of the phosphinositide-3-kinase/Akt pathway reversed the halofuginone-induced cell survival, suggesting this pathway's involvement in mediating halofuginone's effects on survival. Thus, in addition to its known role in inhibiting fibrosis and inflammation, halofuginone plays a direct role in satellite cell activity and survival in muscular dystrophies, regardless of the mutation. These actions are of the utmost importance for improving muscle pathology and function in muscular dystrophies.
Harding, R. L. ; Halevy, O. ; Yahav, S. ; Velleman, S. G. The effect of temperature on proliferation and differentiation of chicken skeletal muscle satellite cells isolated from different muscle types. Physiological Reports 2016, 4 e12770. Publisher's VersionAbstract
Abstract Skeletal muscle satellite cells are a muscle stem cell population that mediate posthatch muscle growth and repair. Satellite cells respond differentially to environmental stimuli based upon their fiber-type of origin. The objective of this study was to determine how temperatures below and above the in vitro control of 38°C affected the proliferation and differentiation of satellite cells isolated from the chicken anaerobic pectoralis major (p. major) or mixed fiber biceps femoris (b.femoris) muscles. The satellite cells isolated from the p. major muscle were more sensitive to both cold and hot temperatures compared to the b.femoris satellite cells during both proliferation and differentiation. The expressions of myogenic regulatory transcription factors were also different between satellite cells from different fiber types. MyoD expression, which partially regulates proliferation, was generally expressed at higher levels in p. major satellite cells compared to the b.femoris satellite cells from 33 to 43°C during proliferation and differentiation. Similarly, myogenin expression, which is required for differentiation, was also expressed at higher levels in p. major satellite cells in response to both cold and hot temperatures during proliferation and differentiation than b. femoris satellite cells. These data demonstrate that satellite cells from the anaerobic p. major muscle are more sensitive than satellite cells from the aerobic b. femoris muscle to both hot and cold thermal stress during myogenic proliferation and differentiation.