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Heat shock protein 60 (Hsp60) is a chaperon localizing in skeletal muscle mitochondria, whose role is poorly understood. This chaperone has been found also in other cellular localizations. In the three years we studied the levels of Hsp60 in fibres of the entire posterior group of hindlimb muscles (gastrocnemius, soleus, and plantaris) in mice after completing a 6-week endurance training program. In this evaluation we correlated Hsp60 levels with the expression of four isoforms of the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α). Moreover, the short-term overexpression of hsp60, achieved by in vitro plasmid transfection was performed to determine whether this chaperon could have a role in the activation of the expression levels of PGC-1α isoforms. The levels of Hsp60 protein were fibre-type specific in the posterior muscles and endurance training increased its content in type I muscle fibers. Concomitantly with the increased levels of Hsp60 released in the blood stream of trained mice, mitochondrial copy number and the expression of three isoforms of PGC-1α increased. Overexpressing hsp60 in cultured myoblasts induced only the expression of PGC-1 α1, suggesting a correlation between Hsp60 overexpression and PGC-1 α1 activation. We are now studying the expression of Hsp60 in the muscles of trained and untrained C26-bearing mice, to understand if Hsp60 over expression may improve muscle performance and reduce cachexia. Four different interleukins have been also studied in cachectic mice, to understand which can be the effect of them on Hsp60 expression both in the tumor mass and the trained muscle.This work was funded by PRIN2009 - Prof. G. Zummo and PRIN2012 - Prof. Farina F., Italian Journal of Anatomy and Embryology, Vol. 121, No. 1 (Supplement) 2016

Exercise is a beneficial adjunct therapy to maintain or enhance quality of life in cancer patients. Recently, few studies demonstrated a correlation between high concentrations of IL-6 and a poor survival. This depends on the equilibrium between the concentrations of IL-6 and sIL-6R. Exercise induces a beneficial increase in circulating IL-6 (1).Fresh fragments of solid C26 tumor were inoculated in healthy 3 months-old mice (n=230, M=115 and F=115). The experimental procedure were 12 weeks long. During the first 6 weeks, mice were randomly assigned to one of the experimental conditions: sedentary (SED) or progressive training (TRP). After the first 6 weeks, all mice were inoculated with a fresh fragment of tumor. All trained adult mice after the tumor inoculation were randomly assigned to a different training program: low intensity training (TRL), moderate intensity training (TRM) and high intensity training (TRH). Mice run 5 days per week on a Rota-Rod following one of the specific training program (TRP ,TRL, TRM and TRH) (2). After tumor inoculation the mice were daily weighted and tumor size monitored until death. Moreover, 8 mice for each group were sacrificed when cachexia occurred (>9% body weight loss), and blood samples were stored for CBA Enhanced flex set flow-cytometric assays (IL-6 and TNF-alpha). The TRM and TRH training protocol performed by trained adult male mice extend the median survival compared to the sedentary adult mice and trained female mice. Interesting the beneficial effect of exercise seemed to be mediated extending the survival days. Significant high blood levels of IL-6 were recorded among the male trained mice (TRM and TRH) groups in comparison with sedentary adult mice and trained female mice (TRM and TRH). The results suggest that endurance exercise as adjuvant therapy is gender and physical training level specific. This effect seems to be mediated by IL-6 blood levels., Italian Journal of Anatomy and Embryology, Vol. 120, No. 1 (Supplement) 2015

Heat shock protein (Hsp60) is a mitochondrial chaperonin whose unconventional cellular localizations and functions are discovered day by day. In the present study, the levels of Hsp60 in fibres of the soleus muscle and its correlation to the expression of four isoforms of peroxisome proliferation-activated receptor-γ (PPAR-γ) coactivator-1α (PGC1α) were investigated in 72 young (7-weeks old) healthy male mice (BALB/c AnNHsd) at baseline and after completing a 6-week endurance training program. The mice were assigned to one of the two experimental groups: SED (sedentary) or TR (trained). Short-term overexpression of hsp60, achieved by in vitro plasmid transfection, was then performed to determine whether this chaperonin could have a role in the activation of the expression levels of PGC-1α isoforms. The levels of Hsp60 protein were fibre-type specific in the posterior muscles at baseline, and endurance training increased its content in type I muscle fibers. Concomitantly with the increased levels of Hsp60 released in the blood stream of trained mice, mitochondrial copy number and the expression of three isoforms of PGC-1α increased. Overexpressing hsp60 in cultured myoblasts induced only the expression of PGC-1 α1, letting us suppose a direct correlation between Hsp60 overexpression and PGC-1 α1 activation. Overall, these results suggest that during endurance training Hsp60 is upregulated and activates the mitochondrial biogenesis pathway, probably as a response to the oxidative stress induced by exercise. This study reveals a molecular response of skeletal muscle to a mechanical stress induced by training which involves the molecular chaperonin Hsp60 and the transcriptional co-activator PGC-1 α1. The role of these proteins in aerobic adaptation and pathological conditions as cancer cachexia warrants further investigations., Italian Journal of Anatomy and Embryology, Vol. 120, No. 1 (Supplement) 2015

Evidence from recent publications indicates that repeated exercise may enhance the quality of life of cancer patients (Maddocks et al., 2012). Regular physical activity may attenuate the adverse effects of cancer therapy, prevent or reverse cachexia and improve survival, although not all the patients are able or willing to undertake programs currently being offered. The aims of this study were to analyze: i) the effects of a progressive endurance exercise (progressive Training, pTR) on survival and cachexia in sedentary (SED) mice inoculated (I) with a fresh fragment of solid C26 tumor [SED-I-pTR; SED-I-SED]; ii) the effect of different protocols of endurance exercise (Trained for 30 min, TR30; Trained for 60 min, TR60; Trained for 120 min, TR120) on survival and cachexia in trained mice inoculated (I) with a fresh fragment of solid C26 tumor [pTR-I-TR30’; pTR-I-TR60’; pTR-I-TR120’]. All the conditions were tested to evaluate the gender (male and female) and age differences (young, 7-weeks old; adult, 3-months old; old, 15-months old). Mice were trained on a rota-rod for 6 weeks (5 times per week). Male sedentary mice (SED-I-SED) showed a higher median survival than sedentary female mice (for each age group); moreover adult mice survive more than sedentary young and old mice (for both gender groups). The endurance training improved the survival of mice in which the tumor was more aggressive (young and old), especially in female mice. Moreover, in the female old mice the progressive training exercise conducted before the inoculation seems to prolong survival. The data suggest that the endurance exercise as adjuvant therapy in cachexia needs to be gender and age specific., Italian Journal of Anatomy and Embryology, Vol 118, No 2 (Supplement) 2013