Aging and increased life expectancy are associated with the progression of chronic metabolic diseases, such as type 2 diabetes, obesity, hypertension, dyslipidemia and cardiovascular conditions. These multifactorial pathologies are complex, often resulting from a combination of genetic and environmental factors, such as physical inactivity and diet. The steady decline of skeletal muscle mass that comes with aging (sarcopenia) is thought to be involved in these metabolic changes, however little is known on how deranged skeletal muscle metabolism influences the development of metabolic disorders.
Pathophysiological framework of skeletal muscle metabolism in aging
The Aging and Muscle Metabolism lab performs translational research projects covering multiple metabolic diseases in human and non-human models, to elucidate molecular mechanisms underlying altered muscle metabolism with aging.
The understanding of the effect of aging and exercise on muscle metabolism is the main theme of our lab. To respond to this quest, we progress through three synchronous aims, which taken together allow an integrative vision.
Schematic representation of our research objectives
AGING & MUSCLE METABOLISM
Aging is associated with alterations in skeletal muscle metabolism. In addition to functional consequences, such as muscle wasting, higher risk of falls and reduced independence for daily living, deranged skeletal muscle metabolism is thought to play a role in age-related metabolic diseases, such as type 2 diabetes and obesity.
Healthy aging encompasses multiple interventions and lifestyle changes, such as eating well, maintaining a social role and exercising regularly. Exercise and regular physical activity have been shown to provide many health benefits, particularly in preventing frequent debilitating diseases such as sarcopenia (i.e. marked loss of skeletal muscle mass) and increasing health quality in addition to lifespan. Exercise markedly improves muscle mass and is thought to reverse, at least partially, metabolic consequences of aging.
The Aging and Muscle Metabolism lab uses clinical interventions, such as exercise programs, to understand mechanisms leading to metabolic consequences of aging and to assess reversibility. Participants in our clinical study encompass active or sedentary adults.
Insulin resistance can be seen as a state in which a cell, an organ, or the whole body, do not respond to normal amounts of insulin and thus requires higher than average levels of circulating insulin to elicit its normal physiological response. It involves defects in multiple organ systems - the muscle, the liver, the pancreas and the adipose tissue- act together to produce abnormal glucose and lipid metabolism.
Insulin resistance is a crucial factor for the development of type 2 diabetes and a major health problem for older adults. It is the principal mechanism by which obesity is considered to increase the risk for type 2 diabetes and is a key feature of the metabolic syndrome. The elevated prevalence of obesity and type 2 diabetes in the older population has important consequences on the morbidity and mortality as well as on the economic burden on our societies.
Controversy currently exists as to whether or not aging contributes to insulin resistance. Many potential factors confound the association between aging and insulin resistance, including obesity and physical activity. In addition, body types and specific lipid depositions may distinctly influence insulin resistance.
Pathophysiology of insulin resistance and type 2 diabetes
BODY COMPOSITION AND ECTOPIC LIPIDS
Body composition, meaning the amount of fat and muscle in the whole body also plays an important role in insulin resistance and metabolic diseases.
Due to its anatomical importance, skeletal muscle accounts for about 80% of the insulin stimulated glucose disposal. Sarcopenia consequences, such as frailty and mobility impairment, are implicated in falls, loss of independence and cost of care. In addition to preventive and therapeutic benefits, physical activity and exercise interventions have been proven to be cost-effective.
Specific adipose tissue depots distinctly influence insulin resistance, such as visceral adipose tissue and intermuscular fat accumulation. Ectopic lipid depositions, defined as an excess accumulation of triglycerides in non adipose tissues such as in the liver (intra-hepatic lipids, IHCL) and within the muscle fibers (intramyocellular lipids, IMCL), are positively associated with obesity and insulin resistance. Furthermore, the accumulation of intracellular lipids is often cited as being a key determinant in the underlying mechanisms of insulin resistance. In addition of playing an important role in obesity and type 2 diabetes, these ectopic fat depositions are also observed in common conditions such as aging and physical inactivity.
Our group uses in vivo and ex-vivo techniques to assess the different components of these fat depositions and how they relate to insulin resistance.
Example of spectra acquired with proton magnetic resonsance spectroscopy in a muscle of the lower leg.
Example of the use of magnetic resonance imaging to quantify specific abdominal fat depositions.
EXERCISE EFFICIENCY AND METABOLIC FLEXIBILITY
In response to different environmental and physiological situations, different energy sources are used. A metabolically healthy individual is metabolically flexible and thus has the ability to switch from predominantly fat utilization to carbohydrate utilization when going from the fasted to the fed state. Obesity and type 2 diabetes blunt this capacity.
Different sources of energy are used during an acute bout of exercise depending on the intensity and the duration of the exercise bout, as well as on the environmental factors and the training state of the individual. Our focus is to continue to understand how to maximize metabolic flexibility and how this interacts with exercise efficiency in metabolically compromised individuals and in chronic diseases such as obesity and diabetes.
A volunteer undergoing a graded exercise test
FROM VOLUNTEERS TO CELLS TO MOLECULES: UNDERSTANDING MOLECULAR PATHWAYS IMPACTING MUSCLE METABOLISM
At the cellular level, substrate usage depends on multiple factors, among the principal ones are the mitochondria (power house of the cell). Mitochondria are cellular organelles that produce most of the chemical energy for cellular sustainment. In muscle, mitochondria are critically needed to generate energy for contraction and thus movement and locomotion. Mitochondria are highly adaptable; they respond to environmental challenges (such as exercise training or nutritional cues) by increasing or decreasing in numbers as well as in their content, and/or becoming more or less efficient.
Mitochondrial dysfunction is proposed to play a central role in the age-related physiological decline. At the cellular level, our focus is to investigate mitochondria functional adaptations through aging and exercise centering on pathways that impact mitochondria content, generation, dynamics and removal of damaged mitochondria (called mitophagy).
Mitochondrial network in one cell
With the implementation of mechanistical models such as the use of zebrafish and cells, the lab is deepening research paradigms on specific pathways and protein targets.
Zebrafish, an ideal model for muscle development
ACTUAL GROUP MEMBERS
Francesca Amati, group leader
|After finishing her MD and specialization in internal medicine and diabetology at the University of Geneva, Francesca obtained her PhD at the University of Pittsburgh in the lab of Bret Goodpaster. The creation of the Aging and Muscle Metabolism lab started with the implementation of the AGIR study, a large clinical study including an exercise intervention. Progressively the lab has grown bonding clinical to biological approaches, thus creating a true translational environment.|
Yoan Arribat, post doctoral fellow
|Following his Master’s degree in Neurosciences and Physiology, Yoan obtained his PhD in Montpellier to decipher the mechanisms involved in Huntington’s disease. He obtained a post-doctoral fellowship from AFM/telethon to investigate neuromuscular disorders in zebrafish. He joined the AMM lab to implement a zebrafish projects to explore adaptation machineries in muscle.|
Sonia Conde Alonso, PhD Student
After a specialization in nutrition, Sonia received her nursing bachelor in Spain. After few years of nursing in UK and Paris, she went back to Spain and pursued her bachelor in Physical Activity & Sport Sciences. After finishing her master at the Institute of Sports Sciences of the University of Lausanne, she started her PhD in the AMM lab focusing on clinical research.
Sylviane Lagarrigue, post doctoral fellow
|Sylviane studied biology at the University of Montpellier where she received her Master's degree. She did her PhD in the lab of Lluis Fajas Coll on the role of the CDK4 kinase in the biology of adipose tissue. Sylviane joined the AMM lab where she developed the human primary cells projects.|
Maxime Moreillon, MD student
After finishing his specialization in Sports Medicine, Maxime is currently doing is doctoral research at the AMM lab while continuing his clinical activity in internal medicine at the University Hospital.
Emannuel Ofori, PhD Student
Emmanuel obtained his bachelor and master’s degree in clinical biochemistry from the University of Ghana. He worked in the Endocrine Laboratory unit of the Korle-Bu Teaching Hospital in Ghana. He was awarded a SWISS Government scholarship to pursue his doctoral training in the AMM lab. His projects combine clinical research and biochemistry.
Sisitha Jayasinghe, post doctoral fellow
|Sisitha obtained his Doctoral Degree in Physiology and Endocrinology from Deakin University in Melbourne Australia. Upon completion of his PhD, he moved to Cornell University in the United states for postdoctoral training in pre-clinical diabetes and cancer biology. He was awarded a Swiss Government Excellence Fellowship to further his postdoctoral training at the AMM lab.|
Dogan Grepper, PhD Student
After obtaining is bachelor in pharmacy and his master in pharmaceutical sciences at the University of Basel, Dogan joined the AMM lab with the goal of pursuing his PhD focusing on the link between diabetes and muscle metabolism.
PAST GROUP MEMBERS
- Nicholas Broskey PhD, Exercise physiologist: After finishing his PhD in the AMM Lab, Nick is currently in a post doctoral position at the Pennington Research institute (link to actual website)
Chiara Greggio PhD, Biologist: After her post doctoral fellowship in the AMM lab, Chiara continues her career in a private company.
William Janssens MS, Exercise specialist: Master did his master research in the AMM lab and is currently a fitness instructor and independent personal trainer.
- Lorena Correa, MS, Exercise physiologist: After visiting the lab in an exchange program, Lorena is currently finishing her PhD in Malaga.
Elvis Carnero PhD, Exercise physiologist: After setting up is lab at the University of Malaga, Elvis performed an Erasmus visit in the AMM lab. While keeping his involvement as a professor and researcher at the University of Malaga, Elvis is currently a visiting scientist at the Translational Research Institute for Metabolism and Diabetes in Orlando (link to actual website)
PUBLICATIONS & FUNDING
- C. Greggio, P. Jha, S.S. Kulkarni, S. Lagarrigue, N.T. Broskey, M. Boutant, X. Wang, S. Conde Alonso, E. Ofori, J. Auwerx, C. Cantó, F. Amati. Enhanced respiratory chain supercomplexes formation in response to exercise in human skeletal muscle. Cell Metab. 2017 Feb 7;25(2):301-311. doi: 10.1016/j.cmet.2016.11.004. Epub 2016 Dec 1. PMID: 27916530.
E.V. Menshikova, V.B. Ritov, J.J. Dubé, F. Amati, M. Stefanovic-Racic, F.G.S. Toledo, P.M. Coen and B.H. Goodpaster. Calorie Restriction-induced Weight Loss and Exercise Have Differential Effects on Skeletal Muscle Mitochondria Despite Similar Effects on Insulin Sensitivity. J Gerontol A Biol Sci Med Sci. 2017 Feb 2. doi: 10.1093/gerona/glw328. PMID: 28158621.
J.J. Dubé, N.T. Broskey, A.A. Despines, M. Stefanovic-Racic, F.G.S. Toledo, B.H. Goodpaster and F. Amati. Muscle characteristics and substrate energetics in lifelong endurance athletes. Med Sci Sports Exerc. 2016 Mar;48(3):472-80. PMID: 26460630.
A.J. Santanasto, P.M. Coen, N.W. Glynn, K.E. Conley, S.A. Jubrias, F.Amati, E.S. Strotmeyer, R. Boudreau, B.H. Goodpaster and A.B. Newman. The Relationship between Mitochondrial Function and Walking Performance in Older Adults with a Wide Range of Physical Function. Exp Gerontol. 2016 Aug;81:1-7. doi: 10.1016/j.exger.2016.04.002 (PMID 27084585)
N.T. Broskey, A. Boss, E.-J. Fares, C. Greggio, G. Gremion, L. Schlüter, D. Hans, R. Kreis, C. Boesch, F. Amati. Exercise Efficiency Relates With Mitochondrial Content and Function in Older Adults. Physiol Rep. 2015 Jun;3(6). PMID: 26059033
A.J. Santanasto, N.W. Glynn, S.A. Jubrias, K.E. Conle, R.M. Boudreau, F. Amati, D.C. Mackey, E.M. Simonsick, E.S. Strotmeyer, P.M. Coen, B.H. Goodpaster, A.B.Newman. Skeletal Muscle Mitochondrial Function and Fatigability in Older Adults. J Gerontol A Biol Sci Med Sci. 2015 Nov;70(11):1379-85. PMID: 25167867.
N.T. Broskey, C. Greggio, A. Boss, M. Boutant, A. Dwyer, L. Schlueter, D.Hans, G. Gremion, R.Kreis. C.Boesch. C. Canto, F. Amati. Skeletal muscle mitochondria in the elderly: effects of physical fitness and exercise training. J Clin Endocrinol Metab, May 2014, 99(5):1852–1861. PMID: 24438376
P.M. Coen, S.A. Jubrias, G. Distefano, F. Amati, D.C. Mackey, N.W. Glynn, T.M. Manini, S.E. Wohlgemuth, C.Leewenburgh, S.R. Cummings, A.B. Newman, L. Ferrucci, F.G. Toledo, E. Shankland, K.E. Conley, B.H. Goodpaster. Skeletal Muscle Mitochondrial Energetics Are Associated With Maximal Aerobic Capacity and Walking Speed in Older Adults. J Gerontol A Biol Sci Med Sci, 2013, April, 68(4): 447-455. PMID: 23051977.
N.T. Broskey, J.Daraspe, B.M. Humbel, F. Amati. Skeletal muscle mitochondial and lipid droplet content assessed with standardized grid sizes for stereology. J Appl Physiol, 2013, Sep; 115(5): 765-70. (PMID: 23788579)[IF 3.434, 2013] J.J. Dubé, K.F. Allison, V. Rousson, B.H. Goodpaster and F. Amati. Exercise Dose and Insulin Sensitivity: Relevance for Diabetes Prevention. Med Sci Sports Exerc. 2012 May, 44(5): 793-799. (PMID: 22051572) [IF 4.475, 2012]
F. Amati, J.J. Dube, E.A. Carnero, M.M. Edreira, P. Chomentowski, P.M. Coen, G.E. Switzer, P.E. Bickel, M. Stefanovic-Racic, F.G. Toledo and B.H. Goodpaster. Skeletal muscle triglycerides, diacylglycerols and ceramides in insulin resistance: Another paradox in endurance-trained athletes? Diabetes, 2011, 60:2588–2597. PMID: 21873552.
COLLABORATIONS & AFFILIATIONS
EXTERNAL SCIENTIFIC COLLABORATIONS
- Chris Boesch and Roland Kreis, Department of Clinical research, MR Spectroscopy and Methodology, University of Bern, Bern
- Cedric Moro, INSERM, Toulouse
- Carles Canto, Nestle Institute of Health, Lausanne
- Johan Auwerx, EPFL, Lausanne
- Andrew Dwyer, Boston College, Boston
- Carles Cantó and Philipp Gut, Nestlé Institute of Health, Lausanne
SCIENTIFIC COLLABORATIONS WITHIN THE UNIVERSITY OF LAUSANNE
- Jean Daraspe and Bruno Humbel, Electron microscopy facility
- Mehdi Tafti, Luc Pellerin and Christian Widman, Department of Physiology
- Zebrafish facility in collaboration with Alexandre Reymond (CIG) and Marie-Catherine Vozenin (CHUV)
- Vincent Gremeaux-Bader and Cyril Besson, Sports Medicine Lab, CHUV
- Didier Hans, Radiology, CHUV
- Leo Schluetter, Cardiologist, Private Practice
- Jean-Pierre Sacco, Let’s go Fitness
- Service of Endocrinology, Diabetology and Metabolism, CHUV
- Service of Sports Medicine, CHUV
- Sport research group/Plateforme de recherche sur le sport, Institute of Sports Sciences, UNIL
- Lausanne Integrative Metabolism Nutrition Alliance (LIMNA)
- Division of Endocrinology and Metabolism, University of Pittsburgh
Some articles/broadcasts about our research
RTS la 1ère, CQFD, Les frileux en vedette, February 20, 2017 (link)
RTS la 1ère, CQFD, Il n’y a pas d’âge pour les bienfaits du sport, December 1, 2016 (link)
RTS, 36.9°, L’Amérique à vélo : l’incroyable défi d’une ex-sédentaire. April 11, 2018 (link)
TSR, 19h30, Le sport a des effets bénéfiques pour les seniors, December 1, 2016 (link)
Sport Medicine Bulletin “Active Voice” March 2016 (link)
Sport Medicine Bulletin “Active Voice” June 2012 (link)
Men’s health magazine Online May 2012 (link)