Exercise-mediated Rescue of Mitochondrial Dysfunctions Driving Insulin Resistance

Mitochondrial Diseases Clinical Trial

— EX-MITO-DYS-IR  

Official title:

Exercise-mediated Rescue of Mitochondrial Derangements Driving Insulin Resistance in Humans (EX-MITO-DYS-IR)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06080594
• Other study ID #: EX-MITO-DYS-IR
• Status: Recruiting
• Phase: N/A
• Start date: August 2024
• Est. completion date: December 2025

Study information

• Verified date: March 2024
• Source: Rigshospitalet, Denmark
• Contact: Matteo Fiorenza, Ph.D.
• Phone: +4535458748
• Email: matteo.fiorenza[@]regionh.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The overarching aim of this intervention study is to interrogate the interconnection between the muscle mitochondrial adaptations and the changes in muscle insulin sensitivity elicited by exercise training in individuals harbouring pathogenic mitochondrial DNA mutations associated with an insulin-resistant phenotype.

In a within-subject parallel-group longitudinal design, participants will undergo an exercise training intervention with one leg, while the contralateral leg will serve as an inactive control. After the exercise intervention, patients will attend an experimental trial including:

• A hyperinsulinemic-euglycemic clamp combined with measurements of femoral artery blood flow and arteriovenous difference of glucose

• Muscle biopsy samples

Description:

Background: Peripheral insulin resistance is a major risk factor for metabolic diseases such as type 2 diabetes. Skeletal muscle accounts for the majority of insulin-stimulated glucose disposal, hence restoring insulin action in skeletal muscle is key in the prevention of type 2 diabetes. Mitochondrial dysfunction is implicated in the etiology of muscle insulin resistance. Also, as mitochondrial function is determined by its proteome quantity and quality, alterations in the muscle mitochondrial proteome may play a critical role in the pathophysiology of insulin resistance. However, insulin resistance is multifactorial in nature and whether mitochondrial derangements are a cause or a consequence of impaired insulin action is unclear. In recent years, the study of humans with genetic mutations has shown enormous potential to establish the mechanistic link between two physiological variables; indeed, if the mutation has a functional impact on one of those variables, then the direction of causality can be readily ascribed. Mitochondrial myopathies are genetic disorders of the mitochondrial respiratory chain affecting predominantly skeletal muscle. Mitochondrial myopathies are caused by pathogenic mutations in either nuclear or mitochondrial DNA (mtDNA), which ultimately lead to mitochondrial dysfunction. Although the prevalence of mtDNA mutations is just 1 in 5,000, the study of patients with mtDNA defects has the potential to provide unique information on the pathogenic role of mitochondrial derangements that is disproportionate to the rarity of affected individuals. The m.3243A>G mutation in the MT-TL1 gene encoding the mitochondrial leucyl-tRNA 1 gene is the most common mutation leading to mitochondrial myopathy in humans. The m.3243A>G mutation is associated with impaired glucose tolerance and insulin resistance in skeletal muscle. Most importantly, insulin resistance precedes impairments of β-cell function in carriers of the m.3243A>G mutation, making these patients an ideal human model to study the causative nexus between muscle mitochondrial dysfunction and insulin resistance. Exercise training is a potent stimulus to enhance muscle insulin action, improve mitochondrial function, and promote mitochondrial proteome remodeling. Accordingly, rescue of mitochondrial dysfunction has been proposed to play a role in the insulin-sensitizing effect of exercise. Yet, numerous mechanisms may contribute to the pathophysiology of insulin resistance and the beneficial effects of exercise may be linked to amelioration of multiple factors, thus challenging the interpretation of the functional significance of improved muscle mitochondrial function per se. Nevertheless, since mitochondrial dysfunction is likely the primary cause of muscle insulin resistance in carriers of the m.3243A>G mutation, prospective studies including an in-depth analysis of the mitochondrial adaptations elicited by exercise training in this cohort of patients may offer a unique opportunity to identify those mitochondrial derangements that, once rescued, drive enhancements in insulin sensitivity.

Objective: To study the effects of exercise training on muscle insulin sensitivity, muscle mitochondrial function, and the muscle mitochondrial proteome in individuals harboring pathogenic mitochondrial DNA (mtDNA) mutations associated with an insulin-resistant phenotype.

Study design: Within-subject parallel-group longitudinal study in individuals with pathogenic mtDNA mutations undergoing an exercise training intervention with one leg (contralateral leg as inactive control).

Endpoint: Differences between the trained and the untrained leg.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 15
• Est. completion date: December 2025
• Est. primary completion date: December 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Known m.3243A>G mutation in the MT-TL1 gene encoding the mitochondrial leucyl-tRNA 1 gene

• Other known mtDNA point mutations

Exclusion Criteria:

• Use of antiarrhythmic medications or other medications which, in the opinion of the investigators, have the potential to affect outcome measures.

• Diagnosed severe heart disease, dysregulated thyroid gland conditions, or other dysregulated endocrinopathies, or other conditions which, in the opinion of the investigators, have the potential to affect outcome measures.

• Pregnancy

Related Conditions & MeSH terms

• Insulin Resistance
• Mitochondrial Diseases
• Mitochondrial Disorders
• Mitochondrial Myopathies

Intervention

Behavioral:
• High-intensity exercise training
Eight sessions of high-intensity knee extensor exercise are conducted on separate days over a 2-week period.

Locations

Country	Name	City	State
Denmark	Rigshospitalet	Copenhagen

Sponsors (2)

Lead Sponsor	Collaborator
Rigshospitalet, Denmark	University of Copenhagen

Country where clinical trial is conducted

Denmark, 

References & Publications (17)

DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. 1991 Mar;14(3):173-94. doi: 10.2337/diacare.14.3.173. — View Citation

DeFronzo RA, Gunnarsson R, Bjorkman O, Olsson M, Wahren J. Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest. 1985 Jul;76(1):149-55. doi: 10.1172/JCI111938. — View Citation

DeFronzo RA, Simonson D, Ferrannini E. Hepatic and peripheral insulin resistance: a common feature of type 2 (non-insulin-dependent) and type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1982 Oct;23(4):313-9. doi: 10.1007/BF00253736. — View Citation

Deshmukh AS, Steenberg DE, Hostrup M, Birk JB, Larsen JK, Santos A, Kjobsted R, Hingst JR, Scheele CC, Murgia M, Kiens B, Richter EA, Mann M, Wojtaszewski JFP. Deep muscle-proteomic analysis of freeze-dried human muscle biopsies reveals fiber type-specific adaptations to exercise training. Nat Commun. 2021 Jan 12;12(1):304. doi: 10.1038/s41467-020-20556-8. Erratum In: Nat Commun. 2021 Mar 5;12(1):1600. — View Citation

Diaz-Vegas A, Sanchez-Aguilera P, Krycer JR, Morales PE, Monsalves-Alvarez M, Cifuentes M, Rothermel BA, Lavandero S. Is Mitochondrial Dysfunction a Common Root of Noncommunicable Chronic Diseases? Endocr Rev. 2020 Jun 1;41(3):bnaa005. doi: 10.1210/endrev/bnaa005. — View Citation

DiMauro S. Mitochondrial myopathies. Curr Opin Rheumatol. 2006 Nov;18(6):636-41. doi: 10.1097/01.bor.0000245729.17759.f2. — View Citation

Elliott HR, Samuels DC, Eden JA, Relton CL, Chinnery PF. Pathogenic mitochondrial DNA mutations are common in the general population. Am J Hum Genet. 2008 Aug;83(2):254-60. doi: 10.1016/j.ajhg.2008.07.004. — View Citation

Frederiksen AL, Jeppesen TD, Vissing J, Schwartz M, Kyvik KO, Schmitz O, Poulsen PL, Andersen PH. High prevalence of impaired glucose homeostasis and myopathy in asymptomatic and oligosymptomatic 3243A>G mitochondrial DNA mutation-positive subjects. J Clin Endocrinol Metab. 2009 Aug;94(8):2872-9. doi: 10.1210/jc.2009-0235. Epub 2009 May 26. — View Citation

Gorman GS, Schaefer AM, Ng Y, Gomez N, Blakely EL, Alston CL, Feeney C, Horvath R, Yu-Wai-Man P, Chinnery PF, Taylor RW, Turnbull DM, McFarland R. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol. 2015 May;77(5):753-9. doi: 10.1002/ana.24362. Epub 2015 Mar 28. — View Citation

Hesselink MK, Schrauwen-Hinderling V, Schrauwen P. Skeletal muscle mitochondria as a target to prevent or treat type 2 diabetes mellitus. Nat Rev Endocrinol. 2016 Nov;12(11):633-645. doi: 10.1038/nrendo.2016.104. Epub 2016 Jul 22. — View Citation

Lindroos MM, Majamaa K, Tura A, Mari A, Kalliokoski KK, Taittonen MT, Iozzo P, Nuutila P. m.3243A>G mutation in mitochondrial DNA leads to decreased insulin sensitivity in skeletal muscle and to progressive beta-cell dysfunction. Diabetes. 2009 Mar;58(3):543-9. doi: 10.2337/db08-0981. Epub 2008 Dec 10. — View Citation

Meex RC, Schrauwen-Hinderling VB, Moonen-Kornips E, Schaart G, Mensink M, Phielix E, van de Weijer T, Sels JP, Schrauwen P, Hesselink MK. Restoration of muscle mitochondrial function and metabolic flexibility in type 2 diabetes by exercise training is paralleled by increased myocellular fat storage and improved insulin sensitivity. Diabetes. 2010 Mar;59(3):572-9. doi: 10.2337/db09-1322. Epub 2009 Dec 22. — View Citation

O'Rahilly S. "Treasure Your Exceptions"-Studying Human Extreme Phenotypes to Illuminate Metabolic Health and Disease: The 2019 Banting Medal for Scientific Achievement Lecture. Diabetes. 2021 Jan;70(1):29-38. doi: 10.2337/dbi19-0037. — View Citation

Parish R, Petersen KF. Mitochondrial dysfunction and type 2 diabetes. Curr Diab Rep. 2005 Jun;5(3):177-83. doi: 10.1007/s11892-005-0006-3. — View Citation

Petersen MC, Shulman GI. Mechanisms of Insulin Action and Insulin Resistance. Physiol Rev. 2018 Oct 1;98(4):2133-2223. doi: 10.1152/physrev.00063.2017. — View Citation

Saleheen D, Natarajan P, Armean IM, Zhao W, Rasheed A, Khetarpal SA, Won HH, Karczewski KJ, O'Donnell-Luria AH, Samocha KE, Weisburd B, Gupta N, Zaidi M, Samuel M, Imran A, Abbas S, Majeed F, Ishaq M, Akhtar S, Trindade K, Mucksavage M, Qamar N, Zaman KS, Yaqoob Z, Saghir T, Rizvi SNH, Memon A, Hayyat Mallick N, Ishaq M, Rasheed SZ, Memon FU, Mahmood K, Ahmed N, Do R, Krauss RM, MacArthur DG, Gabriel S, Lander ES, Daly MJ, Frossard P, Danesh J, Rader DJ, Kathiresan S. Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity. Nature. 2017 Apr 12;544(7649):235-239. doi: 10.1038/nature22034. — View Citation

Zabielski P, Lanza IR, Gopala S, Heppelmann CJ, Bergen HR 3rd, Dasari S, Nair KS. Altered Skeletal Muscle Mitochondrial Proteome As the Basis of Disruption of Mitochondrial Function in Diabetic Mice. Diabetes. 2016 Mar;65(3):561-73. doi: 10.2337/db15-0823. Epub 2015 Dec 30. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Leg muscle mass	Leg muscle mass is determined by dual-energy X-ray absorptiometry	Baseline
Primary	Skeletal muscle insulin sensitivity	Insulin-stimulated muscle glucose uptake is determined by the hyperinsulinemic-euglycemic clamp method integrated with measurements of femoral artery blood flow and arteriovenous difference of glucose	90-150 minutes after initiation of a hyperinsulinemic euglycemic clamp
Primary	Muscle mitochondrial respiration	Mitochondrial O2 flux is measured by high-resolution respirometry in permeabilized fibers from muscle biopsy samples	Baseline
Primary	Muscle mitochondrial reactive oxygen species (ROS) production	Mitochondrial H2O2 emission rates are measured by high-resolution fluorometry in permeabilized fibers from muscle biopsy samples	Baseline
Primary	Muscle mitochondrial proteome	Mitochondrial proteome signatures are determined by mass spectrometry-based proteomics in muscle biopsy samples	Baseline
Secondary	Muscle mtDNA heteroplasmy	mtDNA mutation load is measured in muscle biopsy samples from the patients with mitochondrial myopathy	Baseline
Secondary	Muscle insulin signaling	Insulin-mediated changes in the abundance of (phosphorylated) proteins modulating insulin action are measured by immunoblotting in muscle and fat biopsy samples	Before (baseline) and 150 minutes after initiation of the hyperinsulinemic-euglycemic clamp
Secondary	Muscle integrated stress response signaling proteins	Abundance of (phosphorylated) proteins governing the integrated stress response pathway is measured by immunoblotting in muscle biopsy samples.	Baseline
Secondary	Muscle integrated stress response genes	mRNA content of genes governing the integrated stress response pathway is measured by Real-Time PCR in muscle biopsy samples.	Baseline
Secondary	Muscle release of FGF21 and GDF15	Skeletal muscle production of FGF21 and GDF15 is determined by measurements of femoral artery blood flow and arteriovenous difference of plasma FGF21 and GDF15	Before (baseline) and 0-150 minutes after initiation of the hyperinsulinemic-euglycemic clamp
Secondary	Whole-body insulin sensitivity	Whole-body insulin sensitivity is determined by the hyperinsulinemic-euglycemic clamp method	90-150 minutes after initiation of a hyperinsulinemic euglycemic clamp