The Impact of Physical Activity and Antioxidants on Tumor-Skeletal Muscle Crosstalk during Cancer

300 Pages·2017·11.97 MB·English

by  Mohamad Assi

The Impact of Physical Activity and Antioxidants on
Tumor-Skeletal Muscle Crosstalk during Cancer:
Deciphering Signaling Pathways Involved in Tumor
Growth and Muscle Wasting
Mohamad Assi
To cite this version:
MohamadAssi. TheImpactofPhysicalActivityandAntioxidantsonTumor-SkeletalMuscleCrosstalk
during Cancer: Deciphering Signaling Pathways Involved in Tumor Growth and Muscle Wasting.
Education. Université Rennes 2, 2016. English. ￿NNT: 2016REN20055￿. ￿tel-01587650￿
HAL Id: tel-01587650
https://theses.hal.science/tel-01587650
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THESE / UNIVERSITE RENNES 2 présentée par
Mohamad Assi
sous le sceau de l’Université Bretagne Loire

pour obtenir le titre de
Préparée au laboratoire Mouvement, Sport, Santé
DOCTEUR DE L’UNIVERSITE DE RENNES 2
M2S (EA1274, Rennes)
Mention : STAPS
Ecole doctorale Vie-Agro-Santé (VAS)

Thèse soutenue le 08 Décembre 2016
Devant le jury composé de :

The Impact of Physical Pr. Marc FRANCAUX
Directeur de recherches et professeur,
Université Catholique de Louvain, Belgique /rapporteur

Activity and Antioxidants Pr. Stéphane SERVAIS
Professeur, Université François Rabelais-Tours,
France /rapporteur
on Tumor-Skeletal Muscle
Pr. Odile SERGENT
Professeur, Université Rennes 1, France /examinatrice
Crosstalk during Cancer
Pr. Françoise REDINI
Directrice de recherche et professeur, Université Nantes,
France/examinatrice

Deciphering Signaling Pathways Involved Dr. Adrien ROSSARY
Maitre de conférences, Université Clermont-Ferrand,
in Tumor Growth and Muscle Wasting France /examinateur

Dr. Amélie REBILLARD
Maitre de conférences/HDR, Université Rennes 2,
France/Directeur de thèse
Assi, Mohamad. The Impact of Physical Activity and Antioxidants on Tumor-Skeletal Muscle Crosstalk during Cancer :
Deciphering Signaling Pathways Involved in Tumor Growth and Muscle Wasting - 2016
All Our Dreams Can Come
True, If We Have The Courage
To Pursue Them.

Assi, Mohamad. The Impact of Physical Activity and Antioxidants on Tumor-Skeletal Muscle Crosstalk during Cancer :
Deciphering Signaling Pathways Involved in Tumor Growth and Muscle Wasting - 2016
Assi, Mohamad. The Impact of Physical Activity and Antioxidants on Tumor-Skeletal Muscle Crosstalk during Cancer :
Deciphering Signaling Pathways Involved in Tumor Growth and Muscle Wasting - 2016
Acknowledgments
I will start this section by gratefully thanking the jury members for accepting to examine
my Ph.D. work. Namely, Professor Marc Francaux form the University Catholique de Louvain at
Belgium and Professor Stéphane Servais from the University Francois Rabelais-Tours, for
accepting to report this manuscript. Also, I would like to thank Professor Francoise Redini from
the University of Nantes, Professor Odile Sergent from the University of Rennes 1 and Doctor
Adrien Rossary from the University of Clermont-Ferrand, for accepting to be among the jury
members.
Many thanks for the previous director of the laboratory “Movement, Sport and health
Sciences” (M2S), Paul Delamarche and for the actual director Benoit Bideau, for receiving me
as a member of the M2S family.
Today, if pursuing a career of a researcher is not a dream anymore, it is in a major part due
to Amélie Rebillard who believed in my competences and capacities to conduct this work. I would
like to sincerely thank Amélie for her in-science passion, patience, support, motivation and positive
energy. From you I learned that we can find a solution for every complicated problem; to never
give-up or despair when we fail to obtain positive results (recurrent phenomenon among Ph.D.
students); to never neglect literature and reading at the expense on performing experiments; and to
explore new fields and ideas, where others don’t dare, which is the real meaning of research and
being a researcher. I can say that in addition to the phenotypic changes that I have undergone during
these three years, where my beard started to grow spontaneously, I have also gained in maturity at
both scientific and personal plan.
I also appreciated my discussions with Frédéric Derbré, who transmitted to me the passion
to train mice on treadmill and to explore muscle physiology. How can I forget the animated talks
with Nicolas Pierre on RNA extraction and PCR?! But also the great moments of jokes and laughs
that we have shared with the future doctor Kévin Nay. It was a pleasure to share with you my
laboratory experiments, meals and after-noon jogging, even if I was unlikely to follow the rhythm
of Frédéric and Nicolas when they were decided to do fractioned exercise!
Although I did not understand exactly what the “Biomechanics guys” Camille, Pierre (also
known as, Plantouille), Sébastien, Rémy and Sean, were trying to do during these three years, I
often saw them seated in front of their computers, while I was shuttling between my office, the
biochemistry Lab, the histopathology platform and the animal care facility. However, I enjoyed
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Assi, Mohamad. The Impact of Physical Activity and Antioxidants on Tumor-Skeletal Muscle Crosstalk during Cancer :
Deciphering Signaling Pathways Involved in Tumor Growth and Muscle Wasting - 2016
Acknowledgments
our coffee breaks to discuss golf with Camille, politics with Pierre and English with Sean! I would
say that the concept of “foot-chaise” (playing football while seating on the chair in your office)
was innovating and funny, apart the pain that I felt the next day of the match. A special thank for
the road partner Jordan with whom I passed more than two weeks of daily travel Rennes-Nantes,
to perform radiotherapy on mice. I think that I am a fan of your coaching spirit, especially when
you try to gently communicate with your mice and motivate them to pursue the exercise till the
end.
I would like to thank Dany and Luz for their help and technical advices in animal handling,
gavage, injections and sacrifice. I appreciated chemistry discussions with Brice, which were useful
in performing my cell culture experiments. I am also thankful for the Master’s students Florian,
Moussa and Suzanne for their technical help but also for the energy and the positive ambiance
that they deployed in the laboratory, it was a pure pleasure for me to work with such motivated
students. I also hope a good luck for the new Ph.D. students Charles and Suzanne in their projects
and certainly a lot of scientific publications.
My best friends, Ali Farhat, Mohamad Chamas, Stanlislas Zafihita and Yvan Dietrich,
I met you at different moments in my life; Ali and Mohamad we shared the same bench for several
years at the school and the university in Lebanon; Since my arrival to France, I first met Stanlislas
during my Master’s studies at the Réunion Island and, then, Yvan at the Veterinary School of
Nantes. Because of you I knew that true friendship exits and I simply want to thank each one of
you.
I address my gratitude to my mother Abla and father Nabil for their unconditional love and
support. I have the chance to be born in a family that encourages their children to learn science and
provides them with all the means to realize their own ambitions. This work is the culmination of
several years of study, research, perseverance and patience; thus, I dedicate it for them as a sign of
recognition. Finally, I want to thank my brothers Ali, Hassan and Hussein for being a part of my
life and making it more joyful and meaningful.

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Assi, Mohamad. The Impact of Physical Activity and Antioxidants on Tumor-Skeletal Muscle Crosstalk during Cancer :
Deciphering Signaling Pathways Involved in Tumor Growth and Muscle Wasting - 2016
This work is dedicated to:
All those who fought cancer: either lost their battle or survived…
My parents Abla and Nabil
My brothers Ali, Hassan and Hussein
My small country Lebanon

Assi, Mohamad. The Impact of Physical Activity and Antioxidants on Tumor-Skeletal Muscle Crosstalk during Cancer :
Deciphering Signaling Pathways Involved in Tumor Growth and Muscle Wasting - 2016
Assi, Mohamad. The Impact of Physical Activity and Antioxidants on Tumor-Skeletal Muscle Crosstalk during Cancer :
Deciphering Signaling Pathways Involved in Tumor Growth and Muscle Wasting - 2016
Table of Content

A-Introduction and Literature Overview
-Introduction………………………………………………………………………………….03
Chapter I. Reactive Oxygen Species
1. Reactive oxygen and nitrogen species…………………………………………………….. 09
2. Antioxidant defense……………………………………………………………………….. 11
2.1. Enzymatic antioxidant system…………………………………………………………….. 11
2.2. Non-enzymatic: low molecular weight antioxidants and micronutrients………………… 15
3. Oxidative stress and related macromolecules damage………………………………….. 19
3.1. Lipid peroxidation………………………………………………………………………... 21
3.2. Protein oxidation and peroxidation……………………………………………………….. 22
3.3. Oxidative DNA damage………………………………………………………………….... 22
4. Biological role of ROS……………………………………………………………………...... 23
Chapter II. The Role of ROS in Cancer
1. Oxidative stress and cancer: an introduction……………………………………………. 29
2. Sources of ROS in cancer…………………………………………………………………. 30
2.1. ROS-producing enzymes………………………………………………………………….. 31
2.2. Mitochondrial ROS generation………………………………………………………….... 34
3. Antioxidant defense in cancer…………………………………………………………….. 36
4. The double face of ROS in cancer………………………………………………………... 38
4.1. Mechanisms promoting tumor growth and progression…………………………………. 38
4.2. Mechanisms suppressing cancer growth and progression………………………………….. 42
Chapter III. The Role of ROS in Cancer-Related Muscle Wasting
1. Defining cancer cachexia………………………………………………………………....... 51
2. Muscle wasting: key feature of cachexia………………………………………………….. 52
3. Tumor-muscle crosstalk: a principle axis for ROS production and muscle wasting….. 53
4. Sources of ROS in cancer-related muscle wasting……………………………………….. 55
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Assi, Mohamad. The Impact of Physical Activity and Antioxidants on Tumor-Skeletal Muscle Crosstalk during Cancer :
Deciphering Signaling Pathways Involved in Tumor Growth and Muscle Wasting - 2016
Table of Content
4.1. ROS-producing enzymes………………………………………………………………….... 55
4.2. Mitochondrial dysfunction……………………………………………………………….... 58
5. Defective antioxidant response……………………………………………………………. 59
6. ROS-dependent mechanisms in cancer-related muscle wasting……………................... 61
6.1. Anabolic pathways……………………………………………………………………….... 61
6.2. Catabolic pathways……………………………………………………………………….. 63
7. Tumor-muscle crosstalk: what about adjuvant therapies?.................................................. 67
Chapter IV. Physical Activity in Cancer and Related Muscle Wasting
1. Cancer progression, muscle wasting and related physical inactivity…………………… 73
2. Molecular mechanisms modulated by physical activity in healthy conditions………... 74
2.1. Antioxidant response, mitochondrial biogenesis and angiogenesis……………………… 74
2.2. Insulin sensitivity, hormonal changes and muscle-related secretory phenotype…………. 76
3. Exercise-oncology: the impact of physical activity on cancer progression……………. 79
4. Paucity of data: the impact of physical activity on intramuscular cancers, taking
liposarcoma as an example…………………………………………………………………… 85
5. Limited application of physical activity in cancer cachectic patients: need for an alternative
solution………………………………………………………………………….......................... 89
Chapter V. Antioxidants in Cancer and Related Muscle Wasting
1. The use of antioxidants in cancer and related cachexia…………………………… 93
2. Antioxidant vitamins…………………………………………………………………….. 95
3. Polyphenols……………………………………………………………………………….. 98
4. Oligoelements: zinc and selenium………………………………………………………… 101
5. Antioxidant mixture and pharmacological agents……………………………………...... 104
B- Aims of the Thesis………………………………………………………….....111
C- Experimental Studies and Personal Contribution
- Preview on the First Experimental Study………………………………………………..... 115
- First Experimental Study: Maintaining a regular physical activity promotes tumor growth
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Assi, Mohamad. The Impact of Physical Activity and Antioxidants on Tumor-Skeletal Muscle Crosstalk during Cancer :
Deciphering Signaling Pathways Involved in Tumor Growth and Muscle Wasting - 2016