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Mechanisms of Mitochondrial Myopathy

Award Number: F32AR057619
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2011
PERIOD OF PERFORMANCE END DATE: 03/31/2014

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Mechanisms of Mitochondrial Myopathy - DESCRIPTION (provided by applicant): Mitochondrial myopathies are diseases related to dysfunction of the mitochondrial respiratory chain. Defective muscle function is common in mitochondrial disorders and at present effective treatment is lacking. While the knowledge base about genetic mutations as a cause for mitochondrial myopathies is increasing, little is known about how mitochondrial dysfunction actually leads to impaired muscle function. Elucidation of these causative mechanisms will assist in the development of pharmacological treatment that could increase the quality of life of individuals with these diseases. The ultimate goal of this project is to improve the treatment of mitochondrial myopathies and, in the longer perspective, also treatment of defects in other organs affected by human mitochondrial dysfunction. Preliminary data indicate that changes in intracellular calcium (Ca2+) handling play a key role in the contractile dysfunction, and a novel way to treat these diseases has been postulated. Three Specific Aims will be used to study the mechanisms underlying the defective muscle function in mitochondrial disorders in specifically designed mouse models and in human muscle biopsies supplied to the host laboratory: 1) Examine global Ca2+ handling and force in isolated skeletal muscle cells of mouse models of mitochondrial myopathy and their controls. Measure the expression of Ca2+ handling proteins in mouse disease models and their controls. Proteins identified as altered by disease will then be examined in muscle biopsies from patients with mitochondrial myopathies. 2) Examine the changes in mitochondrial Ca2+ uptake in models of mitochondrial myopathy and their relation to opening of the mitochondrial permeability transition pore (MPTP). Identify MPTP proteins modified by disease in mouse models and subsequently investigate human samples for the same alterations. 3) Determine whether disease progression can be halted and muscle function recovered by pharmacological inhibition of mitochondrial Ca2+ uptake in mouse models. This translational approach between mouse models and human mitochondrial myopathy patients will lead to a better understanding of factors that impair contractile function and open up new strategies for treatment. PUBLIC HEALTH RELEVANCE: Defective muscle function is common in people with mitochondrial myopathies. While the knowledge base about genetic mutations as a cause for mitochondrial myopathies is increasing, little is known about how mitochondrial dysfunction actually leads to impaired muscle function. The proposed project aims to elucidate causative mechanisms and to assist in the development of pharmacological treatment that could increase the quality of life of individuals with these diseases.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2017 ( Subtotal = -$7,850 )
2017	2013	KAROLINSKA INST	SOLNAVAGEN 1	SOLNA		17165		SWE	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	9/14/2017	EXTENSION WITH OR WITHOUT FUNDS	-$7,850
														Subtotal = -$7,850

Issue Date FY: 2013 ( Subtotal = $53,942 )
2013	2013	KAROLINSKA INSTITUTE, RYLCAR INST OF MEDICINE & SURGERY	DEPT OF NEUROSCIENCE S-171 77	STOCKHOLM				SWE	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	9/3/2013	EXTENSION WITH OR WITHOUT FUNDS	$7,850
2013	2013	KAROLINSKA INSTITUTE	Eulers vag 8	Stockholm				SWE	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	5/21/2013	NON-COMPETING CONTINUATION	$46,092
														Subtotal = $53,942

Issue Date FY: 2012 ( Subtotal = $52,190 )
2012	2012	KAROLINSKA INSTITUTE, RYLCAR INST OF MEDICINE & SURGERY	DEPT OF NEUROSCIENCE S-171 77	STOCKHOLM				SWE	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	4/12/2012	NON-COMPETING CONTINUATION	$7,850
2012	2012	KAROLINSKA INSTITUTE	Eulers vag 8	Stockholm				SWE	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	4/12/2012	NON-COMPETING CONTINUATION	$44,340
														Subtotal = $52,190

Issue Date FY: 2011 ( Subtotal = $48,398 )
2011	2011	KAROLINSKA INSTITUTE, RYLCAR INST OF MEDICINE & SURGERY	DEPT OF NEUROSCIENCE S-171 77	STOCKHOLM				SWE	Arthritis, Musculoskeletal and Skin Diseases Research	002	1	3/29/2011	NEW	$7,850
2011	2011	KAROLINSKA INSTITUTE	Eulers vag 8	Stockholm				SWE	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	3/28/2011	NEW	$0
2011	2011	KAROLINSKA INSTITUTE	Eulers vag 8	Stockholm				SWE	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	3/28/2011	NEW	$39,756
2011	2011	KAROLINSKA INSTITUTE	Eulers vag 8	Stockholm				SWE	Arthritis, Musculoskeletal and Skin Diseases Research	003	1	5/18/2011	NEW	$792
														Subtotal = $48,398

Grand Total All Awards = $146,680

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Mechanisms of Mitochondrial Myopathy

Award Number: F32AR057619

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2011

PERIOD OF PERFORMANCE END DATE: 03/31/2014

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