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Assessing and Alleviating Skeletal Muscle Ca2+ Handling Dysfunction in Sarcopenia

Award Number: R01AR069577
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY The progressive loss of skeletal muscle mass and strength, a condition known as sarcopenia, is perhaps the most debilitating age-associated alteration. In sarcopenia, muscle strength/power decrease significantly more than muscle mass itself, suggesting that it is the overall quality of the muscle that is affected and not only the size or quantity of muscle. Muscle fatigue occurs when the intended physical activity can no longer be continued or is perceived as involving excessive effort. Unfortunately, many elderly suffer from fatigue at physical efforts far less (i.e. walking) than the efforts that are required to induce fatigue in healthy young people. Force generation in muscle is tightly coupled to the release and subsequent re-sequestering of Ca2+ by the sarcoplasmic reticulum (SR). Dysfunction in the Ca2+ handling process has been strongly implicated in the loss of force production in many fatigue producing situations, and it has been suggested that Ca2+ handling impairment may significantly contribute to skeletal muscle failure in sarcopenia. It is also known that tissue hypoxia is greater in aged muscle, and this may exacerbate the mechanisms contributing to Ca2+ handling failure. We have demonstrated that there is a range of reduced O2 availability that will induce “metabolic adaptation” to maintain mitochondrial respiration and energy generation (of which Ca2+ handling may require more than 40%!). Lower intracellular O2 levels in aged muscle will result in a more perturbed intracellular milieu, resulting in an impaired muscle function--in part due to negative effects on the Ca2+ handling process. The interplay between O2 availability and Ca2+ handling on skeletal muscle dysfunction in the elderly has not been carefully investigated, and in particular, treatments for this impairment have not been analyzed. The purpose of this proposed research is to use mouse isolated whole muscle and an intact single skeletal muscle fiber to: 1) test a number of hypotheses centered around the notion that cellular O2 (at levels well above those limiting mitochondrial respiration) induce alterations in the intracellular environment that affect Ca2+ handling in aged muscle, thereby leading to an earlier onset of contractile impairment in hypoxia. And most importantly: 2) test treatments and transgenic models which affect different components of the Ca2+ handling process in an attempt to develop therapeutic strategies for combating O2-related Ca2+ handling dysfunction and thereby alleviate some of the muscle impairment in sarcopenia. Our experimental models allow precise control of the extracellular environment and the intracellular environment can be carefully monitored using non-invasive fluorescent imaging techniques. It is the goal of this research project to use our unique single myofiber model to carefully elucidate the mechanisms by which reduced cellular PO2 in aged muscle impairs Ca2+ handling and contractility, and to subsequently develop strategies to reduce frailty associated Ca2+ handling impairments in older subjects.


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: 2024 ( Subtotal = $0 )
2024	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	10/12/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $330,770 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	5/18/2021	NON-COMPETING CONTINUATION	$23,870
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	12/11/2020	NON-COMPETING CONTINUATION	$306,900
														Subtotal = $330,770

Issue Date FY: 2020 ( Subtotal = $341,000 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	1/8/2020	NON-COMPETING CONTINUATION	$306,900
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	4/3/2020	NON-COMPETING CONTINUATION	$34,100
														Subtotal = $341,000

Issue Date FY: 2019 ( Subtotal = $341,000 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	12/17/2018	NON-COMPETING CONTINUATION	$341,000
														Subtotal = $341,000

Issue Date FY: 2018 ( Subtotal = $341,000 )
2018	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	1/3/2018	NON-COMPETING CONTINUATION	$306,900
2018	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	5/3/2018	NON-COMPETING CONTINUATION	$34,100
														Subtotal = $341,000

Issue Date FY: 2017 ( Subtotal = $341,000 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	3/10/2017	NEW	$341,000
														Subtotal = $341,000

Grand Total All Awards = $1,694,770

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Assessing and Alleviating Skeletal Muscle Ca2+ Handling Dysfunction in Sarcopenia

Award Number: R01AR069577

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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