Subjects With Early-Onset Type 2 Diabetes Show Defective Activation of the Skeletal Muscle PGC-1α/Mitofusin-2 Regulatory Pathway in Response to Physical Activity
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OBJECTIVE: Type 2 diabetes is associated with insulin resistance and skeletal muscle mitochondrial dysfunction. We have found that subjects with early-onset type 2 diabetes show incapacity to increase Vo2max in response to chronic exercise. This suggests a defect in muscle mitochondrial response to exercise. Here, we have explored the nature of the mechanisms involved. RESEARCH DESIGN AND METHODS: Muscle biopsies were collected from young type 2 diabetic subjects and obese control subjects before and after acute or chronic exercise protocols, and the expression of genes and/or proteins relevant to mitochondrial function was measured. In particular, the regulatory pathway peroxisome proliferator–activated receptor γ coactivator (PGC)-1α/mitofusin-2 (Mfn2) was analyzed. RESULTS: At baseline, subjects with diabetes showed reduced expression (by 26%) of the mitochondrial fusion protein Mfn2 and a 39% reduction of the α-subunit of ATP synthase. Porin expression was unchanged, consistent with normal mitochondrial mass. Chronic exercise led to a 2.8-fold increase in Mfn2, as well as increases in porin, and the α-subunit of ATP synthase in muscle from control subjects. However, Mfn2 was unchanged after chronic exercise in individuals with diabetes, whereas porin and α-subunit of ATP synthase were increased. Acute exercise caused a fourfold increase in PGC-1α expression in muscle from control subjects but not in subjects with diabetes. CONCLUSIONS: Our results demonstrate alterations in the regulatory pathway that controls PGC-1α expression and induction of Mfn2 in muscle from patients with early-onset type 2 diabetes. Patients with early-onset type 2 diabetes display abnormalities in the exercise-dependent pathway that regulates the expression of PGC-1α and Mfn2.
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Reduction of the mitochondrial fusion machinery in muscle has been linked to age-related sarcopenia and metabolic diseases like obesity and type 2 diabetes in both rodents and humans.
“Accordingly, the reduction of the mitochondrial fusion machinery in muscle has been linked to age-related sarcopenia [185–187], and metabolic diseases like obesity and type 2 diabetes [188, 189] in both rodents and humans.”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [189]
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- Authors
- Hernández-Alvarez, M. I., Thabit, H., Burns, N., Shah, S., Brema, I., Hatunic, M., Finucane, F., Liesa, M., Chiellini, C., Naon, D., Zorzano, A., & Nolan, J. J.
- Affiliations
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain;
- Trinity College Dublin (IE)
- Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES)
- Università Cattolica del Sacro Cuore (IT)
- Corresponding author
- Nolan, John J.
- ORCID
- Venue
- Diabetes Care
- Publisher
- American Diabetes Association
- Published
- 2009-12-23
- Volume
- 33
- Issue
- 3
- Pages
- 645-651
- ISSN
- 0149-5992 (ISSN-L)
- 1935-5548
- PMC
- PMC2827524
- OpenAlex
- W2122442017
- Cited by
- 189
- References
- 25
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 13 · 2023: 10 · 2022: 9 · 2021: 9 · 2020: 11 · 2019: 13 · 2018: 14 · 2017: 6 · 2016: 16 · 2015: 19 · 2014: 15 · 2013: 21 · 2012: 8
- FWCI
- 4.86
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes Care (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (submittedVersion, cc-by-nc-nd)
- Funders
- European Foundation for the Study of Diabetes
- Novo Nordisk
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- early-onset type 2 diabetes, PGC-1α, mitofusin 2, skeletal muscle mitochondrial function, mitochondrial fusion, exercise response, exercise training, acute exercise, porin, mitochondrial biogenesis, insulin resistance
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Adult, Biopsy, Diabetes Mellitus, Type 2, Female, Gene Expression Regulation, Heat-Shock Proteins, Humans, Male, Membrane Proteins, Motor Activity, Time Factors, Transcription Factors, Signal Transduction, Age of Onset, Muscle, Skeletal, GTP Phosphohydrolases, Mitochondrial Proteins, Young Adult
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