Estrogen, microRNAs and the risk of metabolic dysfunction (EsmiRs) -study

EsmiRs-study investigates the biological mechanisms behind menopause-related adverse health changes. The study uses molecular biology, physiology, endocrinology, and genome-wide sequencing methods in combination with sport and health science research methods.

Project duration

1.9.2017 - 31.8.2022

Core fields of research

Physical activity, health and wellbeing

Research areas

Molecular mechanisms of exercise and health

JYU.Well

Active aging

Physical activity through life span

Physical activity, wellbeing and behaviour change across the life-span

Co-operation

Laakkonen's research group, ERMA, ErROR, PATHWAY, University of Minnesota (USA), Central Finland Wellbeing Services County

Faculty

Faculty of Sport and Health Sciences

Funding

Research Council of Finland

Academy of Finland 2017–2022 (EsmiRs study, PI Eija Laakkonen); Academy of Finland 2020–2024 (MATCH study, PI Eija Laakkonen); Academy of Finland 2020–2023 (ErROR study, PI Sira Karvinen)

Project description

One of the lines of research investigates the role of estradiol in inter-tissue microRNA signaling, and whether this relates to the increased risk of metabolic diseases during aging. The cellular mechanisms behind skeletal muscle aging, such as skeletal muscle apoptosis and its regulation, as well as skeletal muscle steroidogenesis are also studied.

The EsmiRs-study is largely based on the ERMA-study and complemented with new data collection. In addition, in vivo and in vitro design are used. The study has been conducted at the Gerontology Research Center of the Ģ��ֱ��.

The EsmiRs follow-up study repeats the measurements and bio-sampling from the ERMA study and adds the following new measurements.

Fat Oxidation Capacity and Resting Energy Expenditure

Fat oxidation at rest and during exercise and resting energy expenditure are measured with indirect calorimetry. Indirect calorimetry relies on the assumption that fatty acid and carbohydrate oxidation lead to differences in cellular oxygen use and carbohydrate production. With breath-by-breath analysis of the breathing gases, substrate use and energy expenditure can be estimated noninvasively.

Peak Oxygen Consumption

A well-known proxy of cardiorespiratory fitness, peak oxygen consumption primarily results from cardiac output and arteriovenous oxygen difference. In the study, peak oxygen uptake is measured during a maximal graded incremental bicycle ergometer test.

Insulin Sensitivity

Insulin sensitivity is measured with a two hour oral glucose tolerance test during which blood samples are collected in every 30 minutes. Glucose and insulin concentrations are determined from the blood samples and the Matsuda index is calculated to quantify insulin sensitivity. Also, serum metabolites are determined from the samples with NMR spectroscopy to investigate changes in the serum metabolite profile following the glucose ingestion.

Arterial Stiffness

Each heart contraction causes a pulse wave that spreads from the heart to the periphery via arteries. Stiffening arteries increase the pulse wave velocity and change its form. These values can be measured noninvasively with a cuff technique similar to a blood pressure measurement. Results obtained with the noninvasive technique correlate strongly with the direct invasive technique. The study measures arterial stiffness at rest and following an exercise bout.

Dietary Intake and Food Habits

Dietary intake of the participants will also be measured. The participants will record their food intake over three to four day periods before the physiological measurements. Food diaries will be analyzed for energy, macro- and micronutrient intakes. Dietary habits of the participants will also be screened by a questionnaire.

Biochemical Analyses from Blood and Tissue Samples

Blood samples collected over the course of the EsmiRs project are used to study the concentration of leukocytes, total cholesterol, different steroid hormones (e.g. estradiol and testosterone), and various cell-to-cell interaction-related molecular markers. Muscle samples taken as needle biopsies are used to investigate estrogen-associated muscle cell signaling cascades.

MicroRNAs

MicroRNAs, or miRNAs, are short RNA-molecules that participate in the epigenetic regulation of gene reading by binding with their target mRNA-molecules and transiently or permanently blocking corresponding protein translation. miRNAs can act as autocrine regulators inside the cells they have produced or they can be released into the bloodstream to act as endocrine messengers. Released miRNAs can serve as inter-tissue messengers whose concentration and quality can be measured in relation to certain diseases or conditions, including cancer and metabolic dysfunctions.

Next generation sequencing (NGS)

The EsmiRs project uses modern sequencing technology as a way to interpret complex miRNA messaging. Next generation sequencing produces accurate information and the exact sequence of nucleic acid based molecules in a fast and reliable manner. NGS is performed in collaboration with Central Finland Central Hospital’s laboratory of molecular pathology.

Cell Cultures/In Vitro Modelling

Primary myocytes extracted from biopsied tissues are used to study the effects of external estradiol supplements to the cells’ own hormone production in a controlled and adjustable environment.

Histology and Microscopy

Thin cross-sectional sections from the muscle biopsies are used for histology, which aims to find and visualize muscle stem cells’, also known as satellite cells, intracellular lipid accumulation as well as to measure cell size changes within the longitudinal study arm of the ERMA study. The targets are made visible with antibodies and fluorescent labels, which can then be imaged with confocal systems. Images are analyzed with computational software.

Protein Measurements

The biological sample pool contains a large amount of interesting proteins which can be separated and analyzed based on their size or quality. Electrophoresis and antibody-based Western Blots are routinely used to see the changes in the quantity and quality of proteins throughout different hormonal levels.

Quantitative PCR

Polymerase chain reaction (PCR) is used to study the amount of key RNA-molecules produced in the sample. The method can provide information from the reading activity of a gene or about what kind of RNA-transcripts are present in the tissue at a given point. Our research interest centres various miRNAs and, for example, apoptosis related gene transcripts .

ERMA study

The EsmiRs-study is a follow-up study largely based on previous ERMA study. The study has been conducted at the Gerontology Research Center of the Ģ��ֱ��. EsmiRs study will utilize samples from ERMA study for biochemical analysis.

University of Minnesota (USA)

EsmiRs study is done in collaboration with professor Dawn Lowe's research group, that is located at the University of Minnesota, Minneapolis, USA. Docent Eija Laakkonen, the PI of EsmiRs study, has visited Lowe's laboratory several times during the collaboration, and postdoctoral researcher Sira Karvinen spent a year in Lowe's laboratory for postdoctoral training (2016-2017). The collaboration enables EsmiRs project to utilize special skeletal muscle stimulation system ans samples from in vivo models available in Lowe's laboratory.

Central Finland Health Care District

The EsmiRs study utilizes for example the Next Generation Sequencing (NGS) equipment available at the Central Finland Health Care District’s molecular pathology laboratory.

Pesonen, Heidi (Dissertation 25.10.2024): Associations of Aging, Menopause, and Strength Training on Cortical Somatosensory and Motor Functions. JYU dissertations 831. Faculty of Sport and Health Sciences, Ģ��ֱ��, 2024, 105 p. (One of the three papers included was done with the ERMA data. Supervisors K. Waller, I. Tarkka, J. Parkkari, J. Laukkanen).

Hyvärinen, Matti (Dissertation 28.3.2024): Physical activity, menopausal symptoms, and cardiometabolic health during the menopausal transition. JYU dissertations 756. Faculty of Sport and Health Sciences, Ģ��ֱ��, 2024, 77 p. (Four papers included were done with the ERMA and EsmiRs data. Main supervisor E. Laakkonen, co-supervisors J Karvanen and T Rantalainen.)

Karppinen, Jari (Dissertation 16.6.2023): Menopause, physical activity, and whole-body metabolism with an emphasis on resting energy expenditure, fat oxidation, and serum metabolome. JYU dissertations 636. Faculty of Sport and Health Sciences, Ģ��ֱ��, 2023, 153 p. (Three of the four papers included were done with the ERMA and EsmiRs data. Main supervisor E. Laakkonen, co-supervisors U. Kujala and J. Laukkanen.)

Juppi, Hanna-Kaarina (Dissertation 9.6.2023): Associations of the menopausal transition with body composition : Examining the influence of hormonal changes, muscle RNA signaling and lifestyle habits. JYU dissertations 648. Faculty of Sport and Health Sciences, Ģ��ֱ��, 2023, 177 p. (The four papers included were done with the ERMA and EsmiRs data. Main supervisor E. Laakkonen, co-supervisors S. Sipilä and S. Karvinen.)

Ravi, Suvi (Dissertation 21.6.2023): Low energy availability-related conditions in female athletes: Prevalence rates and relationships with health, injuries, and the sports career. JYU dissertations 660. Faculty of Sport and Health Sciences, Ģ��ֱ��, 2023, 153 p. (One of the four papers included was done with the ERMA data. Supervisor J. Parkkari, M. Valtonen, B. Waller, U. Kujala).

Tirkkonen, Anna (Dissertation 20.1.2023): Cognitive and Physical Functions Among Middle-Aged and Older People: A Special Emphasis on Executive Functions and Walking. JYU dissertations 596. Faculty of Sport and Health Sciences, Ģ��ֱ��, 2023, 89 p. (One of the four papers included was done with the ERMA data. Main supervisor S. Sipilä, co-supervisor J. Kulmala.)

Bondarev, Dmitriy (Dissertation 20.5.2022): The Role of Physical Activity in the Relationship between Menopausal Status, Physical Performance and Mental Well-Being. JYU dissertations 515. Faculty of Sport and Health Sciences, Ģ��ֱ��, 2022, 80 p. (Four papers included were done with the ERMA data. Main supervisor S. Sipilä, co-supervisors K. Kokko and T. Finni.)

2024–2025

40. Elisa Toikka. .
39. Kaisa Moilanen.
38. Julia Sivonen. .
37. Marika Puttonen. .
36. Pinja Huovila. .
35. Jaakko Lähde. .
34. Iina Tulomäki.
33. Anni Virkki.
32. Aino Tikka.
31. Jenna Laikola.

2022–2023

30. Katariina Laaksovuori.
29. Tanja Tsokkinen.
28. Viivi Luhtanen. .

2020–2021

27. Kuutti M. .
26. Kansanen M. .
25. Laukka S.
24. Rekiranta S.
23. Jokinen S.
22. Kojo H.
21. Rantanen N. .
20. Jakoaho V. T
19. Lindeman K.

2019–2018

18. Kumpulainen P. K
17. Paavilainen A.
16. Hyvärinen M.
15. Sivonen E.

14. Alapappila M. Liikunta ja vaihdevuodet: aikaisempien liikuntatottumuksien yhteys vaihdevuosioireisiin.
13. Honkonen E.
12. Nyberg L.
11. Saarinen M.
10. Tuominen J.
9. Vilén L.

2017–2016

8. Alm J.
7. Forsius P.
6. Laitinen E.
5. Pahkamäki N.
4. Pitkänen P. Vaihdevuosien, koetun iän ja neuroottisuuden yhteys keski-iän kriisin kokemiseen naisilla.
3. Rikkonen E.
2. Siivonen A-K.
1. Kankare-Anttila N. .

43. Lehti S, Korhonen TM, Soliymani R, Ruhanen H, Lähteenmäki E, Palviainen M, Siljander P, Lalowski M, Käkelä R, Lehti M, Laakkonen EK. The lipidome and proteome of high-density lipoprotein are altered in menopause. J Appl Physiol (1985). 2025 Jun 4. .
42. Juppi HK, Karppinen JE, Laakkonen EK . Menopause and Body Composition: A Complex Field. Semin Reprod Med. 2025 Jun 9. .
41. Kuutti M, Hietavala EM; Juppi HK, Sipilä S, Aukee P, Laakkonen EK. Association of body composition with the symptoms of pelvic floor disorders in middle-aged women: A longitudinal study. Menopause. 2025 Jun 3. .
40. Hyvärinen M, Kankaanpää A, Rantalainen T, Rantanen T, Laakkonen EK, Karavirta L. Body composition and functional capacity as determinants of physical activity in middle-aged and older adults: a cross-sectional analysis. Eur Rev Aging Phys Act. 2025;22(1):6.
39. Karvinen SM, Lähteenmäki E, Hutz B, Juppi HK, Karppinen JE, Kankaanpää A, Lehti M, Laakkonen EK. The acute exercise response of peripheral blood mononuclear cells and their bioenergetic function in women with high and low systemic estradiol levels. Phys Rep. 2025;13:e70296. .
38. Fujita S, Lankila H, Koivunen K, Hakamäki M, Sipilä S, Portegijs E, Rantanen T, Laakkonen EK. Vitamin D sufficiency and its relationship with muscle health across the menopausal transition and aging: Finnish cohorts of middle-aged women and older women and men. Eur J Clin Nutr. 2025 Apr 2. .
37. Suominen T, Rantalainen T, Hyvärinen M, Kujala UM, Aukee P, Tammelin TH, Laakkonen EK, Sipilä S. Associations of habitual skeletal loading with bone changes during the menopausal transition: A follow-up study. Med Sci Sports Exerc. 2025;57(5):942-950. .
36. Lankila H, Kekäläinen T, Hietavala EM, Laakkonen EK. A mediating role of visceral adipose tissue on the association of health behaviours and metabolic inflammation in menopause: a population-based cross-sectional study. Sci Rep. 2025;15(1):1999. .
35. Kuutti M, Hyvärinen M, Lankila H, Aukee P, Hietavala EM, Laakkonen EK. Association of eating behaviour with symptoms of pelvic floor disorders in middle-aged women: An observational study. Women's Health (Lond). 2024;20..
34. Hyvärinen M, Karvanen J, Karppinen JE, Karavirta L, Juppi HK, Tammelin TH, Kovanen V, Laukkanen J, Aukee P, Sipilä S, Rantalainen T, Laakkonen EK. The role of cardiorespiratory fitness and body composition in the association between physical activity and menopausal symptoms. Menopause. 2024;31(9):828-836. .
33. Juppi HK, Korhonen TM, Sievänen T, Kovanen V, Kujala UM, Aukee P, Cronin N, Sipilä S, Karvinen S, Laakkonen EK. Menopausal transition alters female skeletal muscle transcriptome. Translational Exercise Biomedicine. March 13, 2024.
32. Lankila H, Kuutti MA. Kekäläinen T, Hietavala EM, Laakkonen EK. . J Sleep Res. 2024:e14155. doi: 10.1111/jsr.14155.
31. Karppinen JE, Wiklund P, Ihalainen JK, Juppi HK, Isola V, Hyvärinen M, Ahokas EK, Kujala UM, Laukkanen J, Hulmi JJ, Ahtiainen JP, Cheng S, Laakkonen EK. Age but not menopausal status is linked to lower resting energy expenditure. J Clin Endocrinol Metab. 2023; Jun 2:dgad321. doi: 10.1210/clinem/dgad321
30. Hyvärinen M, Karvanen J, Juppi HK, Karppinen JE, Tammelin TH, Kovanen V, Aukee P, Sipilä S, Rantalainen T, Laakkonen EK. . Maturitas. 2023;174:39-47. doi:
29. Karvinen S, Korhonen TM, Sievänen T, Karppinen JE, Juppi HK, Jakoaho V, Kujala UM, Laukkanen JA, Lehti M, Laakkonen EK. . J Extracell Vesicles. 2023 Feb;12(2):e12308. doi: 10.1002/jev2.12308.
28. Kuutti MA, Hyvärinen M, Kauppinen M, Sipilä S, Aukee P, Laakkonen EK.  BJOG. 2023 Jan 19. doi: 10.1111/1471-0528.17397
27. Haapala EA, Lee E, Karppinen JE, Skog H, Valtonen M, Kujala UM, Laukkanen JA, Ihalainen JK, Laakkonen EK.  Sci Rep. 2022;12:21378. doi:10.1038/s41598-022-25795-x
26. Marttila S, Tamminen H, Rajić S, Mishra PP, Lehtimäki T, Raitakari O, Kähönen M, Kananen L, Jylhävä J, Hägg S, Delerue T, Peters A, Waldenberger M, Kleber ME, März W, Luoto R, Raitanen J, Sillanpää E, Laakkonen EK, Heikkinen A, Ollikainen M, Raitoharju E.  Epigenomics. 2022;14(18):1105-1124. doi: 10.2217/epi-2022-0228.
25. Karppinen JE, Juppi H-K, Hintikka J, Wiklund P, Haapala EA, Hyvärinen M, Tammelin TH, Aukee P, Kujala UM, Laukkanen J, Laakkonen EK.  Nutr Metab Cardiovasc Dis. 2022; 32(9):217-67. doi: 10.1016/j.numecd.2022.06.001.
24. Karppinen JE, Törmäkangas T, Kujala UM, Sipilä S, Laukkanen JA, Aukee P, Kovanen V, Laakkonen EK.. Eur J Prev Cardiol. 2022; zwac060,
23. Juppi HK, Sipilä S, Fachada V, Hyvärinen M, Cronin N, Aukee P, Karppinen JE, Selänne H, Kujala UM, Kovanen V, Karvinen S, Laakkonen EK.  Aging Cell. 2022 May 4:e13621. doi: 10.1111/acel.13621.
22. Kekäläinen T, Tammelin TH, Hagger MS, Lintunen T, Hyvärinen M, Kujala UM, Laakkonen EK, Kokko K.  Psychology of Sport and Exercise, 60, May 2022, 102135. .
21. Hyvärinen M*, Juppi H-K*, Taskinen S, Karppinen JE, Karvinen S, Tammelin TH, Kovanen V, Aukee P, Kujala UM, Rantalainen T, Sipilä S, Laakkonen EK.Int J Obes (Lond). 2022;46(3):544-554. doi: 10.1038/s41366-021-01022-x. *equal authorship.
20. Tirkkonen A, Kekäläinen T, Aukee P, Kujala UM, Laakkonen EK, Kokko K, Sipilä S. . Menopause. 2021;29(2):200-209. doi: 10.1097/GME.0000000000001896.
19. Laakkonen EK, Karppinen JE, Lehti S, Lee E, Pesonen E, Juppi HK, Kujala UM, Haapala EA, Aukee P, Laukkanen JA, Ihalainen JK. . Front Endocrinol (Lausanne). 2021;12:765916. doi: 10.3389/fendo.2021.765916.
18. Kekäläinen T, Hietavala E-M, Hakamäki M, Sipilä S, Laakkonen EK, Kokko K. J. Environ. Res. Public Health. 2021;118:7732.
17. Bondarev D, Sipilä S, Finni T, Kujala UM, Aukee P, Kovanen V, Laakkonen EK, Kokko K. BMC Public Health. 2021;21(1):1448.
16. Sillanpää E, Heikkinen A, Kankaanpää A, Paavilainen A, Kujala UM, Tammelin TH, Kovanen V, Sipilä S, Pietiläinen KH, Kaprio J, Ollikainen M, Laakkonen EK. Clin Epigenetics. 2021;13(1):110.
15. Hyvärinen M, Karvanen J, Aukee P, Tammelin TH, Sipilä S, Kujala UM, Kovanen V, Rantalainen T, Laakkonen EK.  Menopause. 2021;28(7):792-799.
14. Pesonen H, Laakkonen EK, Hautasaari P, Aukee P, Kovanen V, Kujala UM, Sipilä S, Finni T, Tarkka IM.  BMC Womens Health. 2021;21(1):133.
13. Karvinen S, Juppi H-K, Le G, Cabelka CA, Mader TL, Lowe DA, Laakkonen EK.  Exp Gerontol. 2021;147:111267.
12. Bondarev D, Finni T, Kokko K, Kujala UM, Aukee P, Kovanen V, Laakkonen EK, Sipilä S.  J Gerontol A Biol Sci Med Sci. 2020;76(9):1587-1590.
11. Ravi S, Kujala UM, Tammelin TH, Hirvensalo M, Kovanen V, Valtonen M, Waller B, Aukee P, Sipilä S, Laakkonen EK. J Clin Med. 2020;9(12):3797.
10. Kekäläinen T, Laakkonen EK, Terracciano A, Savikangas T, Hyvärinen M, Tammelin TH, Rantalainen T, Törmäkangas T, Kujala UM, Alen M, Kovanen V, Sipilä S & Kokko K. . BMC Geriatrics. 2020;20(1):264.
9. Juppi H-K, Sipilä S, Cronin N, Karvinen S, Karppinen JE, Tammelin T, Aukee P, Kovanen V, Kujala UM, Laakkonen EK.  J Clin Med. 2020;9(5):1588.
8. Bondarev D, Sipilä S, Finni T, Kujala UM, Aukee P, Laakkonen EK, Kovanen V, Kokko K.  Menopause. 2020;27(4):398-409.
7. Sipilä S, Törmäkangas T, Sillanpää E, Aukee P, Kujala UM, Kovanen V, Laakkonen EK.  J Cachexia Sarcopenia Muscle. 2020;11(3):698-709.
6. Hyvärinen M, Sipilä S, Kulmala J, Hakonen H, Tammelin TH, Kujala UM, Kovanen V, Laakkonen EK.  J Aging Phys Act. 2019;4:1-11.
5. Karvinen S, Jergenson MJ, Hyvärinen M, Aukee P, Tammelin T, Sipilä S, Kovanen V, Kujala UM, Laakkonen EK.  Front Endocrinol. 2019;10:589.
4. Collins BC, Arpke RW, Larson AA, Baumann CW, Xie N, Cabelka CA, Nash NL, Juppi HK, Laakkonen EK, Sipilä S, Kovanen V, Spangenburg EE, Kyba M, Lowe DL.  Cell Reports. 2019;28(2):368-381.
3. Bondarev D, Laakkonen EK, Finni T, Kokko K, Kujala U, Aukee P, Kovanen V, Sipilä S.  Menopause. 2018;25(12):1432-1441.
2. Kovanen V, Aukee P, PhD, Kokko K, Finni T, Tarkka I, Tammelin T, Kujala UM, Sipilä S, Laakkonen EK.  Menopause. 2018;25(9):1020-1032.
1. Laakkonen EK, Kulmala J, Aukee P, Hakonen H, Kujala UM, Lowe DA, Kovanen V, Tammelin T, Sipilä S.  PLoS ONE. 2017;12(2):e0172054.

Project team

Project leaders

Eija Laakkonen

Associate professor

Project members

External members

Sarianna Sipilä

Dean, Faculty of Sport and Health Sciences

Ģ��ֱ��

Pauliina Aukee

Head of Obstetric and Gynecological Department

Tuija Tammelin

Research Director, LIKES

Katja Kokko

Research Director, Gerontology Research Center

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Urho Kujala

Professor of Sports & Exercise Medicine (emeritus)

Ģ��ֱ��

Jari Laukkanen

Professor, MD, Cardiologist

Maarit Lehti

Senior Researcher, Faculty of Sport and Health Sciences

Ģ��ֱ��

Elina Sillanpää

Associate Professor, Faculty of Sport and Health Sciences

Ģ��ֱ��

Eero Haapala

Senior Lecturer, Associate Professor, Faculty of Sport and Health Sciences

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Research groups

Biogerontology and Translational Health Research – Eija Laakkonen's research group

menopause, estrogen,non-coding RNA-molecules, biomarkers, Lynch syndrome, cancer research

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