Die Auswirkungen von Ostarine und Raloxifen auf die Skelettmuskulatur im ovarektomierten Rattenmodell
by Louis Frederic Noisser
Date of Examination:2024-11-19
Date of issue:2024-11-18
Advisor:PD Dr. Marina Komrakova
Referee:PD Dr. Marina Komrakova
Referee:Prof. Dr. Stephan von Haehling
Persistent Address:
http://dx.doi.org/10.53846/goediss-10839
Files in this item
Name:Noisser_Louis_Dissertation_final ONLINE.pdf
Size:5.93Mb
Format:PDF
The following license files are associated with this item:
Abstract
English
Due to demographic change, age-related diseases such as sarcopenia and osteoporosis are becoming an increasing challenge in Germany. One of the main causes of sarcopenia and muscle weakness is low sex hormone concentrations postmenopausally. Hormone replacement therapy with estrogen or testosterone has been shown to increase muscle mass and function. However, such hormone substitution can lead to serious side effects, particularly on the cardiovascular system. The aim of this study was to find a preventative, medicinal approach to challenge muscle changes caused by hormone deficiency. Raloxifene as a selective estrogen receptor modulator (SERM) and Ostarine as a selective androgen receptor modulator (SARM), as well as their combination, were investigated in an ovariectomized rat model. Both active ingredients are selective hormone receptor modulators and target sex hormone receptors. It is estimated that there could be fewer side effects than with direct hormone substitution. Raloxifene is already approved for postmenopausal osteoporosis and was investigated in this study for its positive effect on muscles. Ostarine is not approved as a drug worldwide, but was able to significantly increase lean body mass in several studies, which could be a promising approach to the prevention and treatment of sarcopenia. The ovariectomized rat was used as an animal model for postmenopausal conditions, as it is widely established as a test animal for researching hormone deficiencies. 60 of the 75 three-month-old female Sprague Dawley rats (Rattus norvegicus) underwent bilateral ovariectomy (OVX) at the start of the experiment. The remaining 15 animals were used as healthy controls (Non OVX). The 60 ovariectomized animals were divided into four treatment groups of 15 animals each and were either left untreated or treated with 0.6 ± 0.1 mg Ostarine (OSTA), 11.1 ± 1.7 mg Raloxifene (RALO) per kilogram of body weight per day or their combination (OSTA+RALO) via the soy-free feed. After the treatment period of 13 weeks, the soleus muscle, gastrocnemius muscle and the uterus were removed and weighed. The longissimus muscle was then collected and the cryopreserved muscles were cut with a cryotome and examined for muscle area and diameter, cell nucleus density and capillarization. The muscle fibers were evaluated for the distribution of fiber types type I, type IIa and type IIb. In addition, the animals were weighed weekly during the experiment and the amount of food consumed was documented. A statistical comparison was made using one-way ANOVA and Tukey test, p < 0.05. Hormone deficiency was successfully induced in the OVX group, as the effects described in the literature, such as weight gain, uterine atrophy and increase in muscle fiber diameter, could be reproduced. The capillary density in the gastrocnemius muscle was increased compared to the Non OVX group. No significant effect on cell nucleus density was observed. During preventive treatment with the drug Raloxifene, it was found that there was no significant difference in feed intake, muscle weight and diameter, muscle area, body weight and nucleus density compared to the healthy Non OVX group despite ovariectomy. Only capillarization was significantly increased under Raloxifene compared to the Non OVX group, but still lower than in the OSTA group. Changes in the OVX group did not occur in the RALO group. This suggests a protective effect against the effects of hormone deficiency. Raloxifene is therefore promising in the treatment of muscle changes caused by postmenopausal hormone deficiency. As expected, the OSTA group showed an anabolic effect on the muscles. This was expressed by increased capillarization. However, an increased nuclear density could not be observed. In addition, an increase in body and muscle weight was observed. However, a significant increase compared to the OVX group could only be observed in isolated cases, so that the effect of Ostarine was not sufficient to counteract the hormone deficiency induced by the ovariectomy. Furthermore, Ostarine showed an undesirable weight gain in the uterus. This observation raises doubts about the selective effect and safety of the active ingredient. When both active ingredients were combined, the effects of ovariectomy on food intake, body weight, muscle weight and capillarization could be prevented, analogous to monotherapy with Raloxifene. However, a significant advantage of the combination of Raloxifene with Ostarine compared to monotherapy with Raloxifene could not be shown. Nuclear density was increased compared to the Non OVX group. In the uterus, the androgenic effect of Ostarine was more prominent in the combination group, which is an undesirable side effect and should be considered as a safety risk. Since Raloxifene has shown a selective and positive effect on the muscles in the present study and is used in osteoporosis patients, it could also be investigated in this context in future clinical studies with regard to its effect on the muscles.
Keywords: Ostarine; Enobosarm; Sacropenia; Raloxifene; SARM; SERM; Osteoporosis
