This project's goal is to elucidate the mechanisms responsible for the decline in skeletal muscle performance with aging. We propose that JP-45 regulates SR Ca2+ release elicited by DHPR-RyR1 coupling and that the JP-45/DHPR11 complex is crucial to the age-dependent decrease in muscle specific force. Hypotheses:
The specific aims will test the hypotheses that JP-45 plays a role in DHPR11 subunit expression and that it's age-dependent down regulation leads to decreased DHPR11 expression, contributing to the decline in SR Ca2+ release and specific force in skeletal muscle fibers from senescent mice.
Aim 1. To establish that JP-45 KO leads to decreased DHPR11 subunit expression by increasing its rate of degradation in skeletal muscle from adult mice. We have previously demonstrated that JP-45 KO leads to decreased DHPR11 subunit expression, charge movement, SR Ca2+ release, and muscle fiber contraction force. However, the mechanism is unknown. Here, we propose that JP-45 down regulation or ablation results in increased 11 subunit degradation meditated by an ubiquitin-proteasome proteolytic pathway.
Aim 2. To determine that age-dependent down regulation of JP-45 expression contributes to excitation- contraction uncoupling (ECU) in senescent mice. These experiments will test the hypothesis that JP45 is downregulates with senescence, leading to decreased DHPR11 expression and ECU. We created a JP-45- viral construct targeted exclusively to skeletal muscle, which can either prevent or restore age-dependent down regulation of JP-45 and, hence, DHPR11 down regulation, rescuing the aging ECC phenotype.
Aim 3. To demonstrate that age-dependent decrease in JP-45 expression contributes to reduced single intact muscle fiber specific force without affecting contractile myofilament sensitivity to Ca2+. In the same single fiber, first intact and then skinned, we will test voltage-dependent and independent properties, respectively, to answer the following questions: (1) Can JP-45 rescue age-dependent loss in contraction specific force? (2) Can it rescue decreases in peak intracellular Ca2+ mobilization with aging? (3) Is the decrease in fiber specific force a consequence of changes in contractile myofilament sensitivity to Ca2+? Aim 4. To demonstrate that JP-45 gene transcription declines with aging, that insulin-like growth factor-1 (IGF-1) regulates JP-45 gene transcription and that IGF-1-induced prevention or restoration of the decline in DHPR 11 subunit expression in aging skeletal muscle requires JP-45. We propose that: (1) JP-45 gene transcription decreases with aging, (2) IGF-1 regulates JP-45 gene transcription, and (3) IGF-1- induced 11 subunit upregulation is precluded by age-dependent JP-45 down regulation and JP-45 KO, supporting the theory that JP-45 protects 11 subunits from poly-ubiquitination and proteasome degradation. We will test this concept using S1S2, a transgenic mouse model that over-expresses IGF-1 in skeletal muscle, crossbred with JP-45KO mice or an IGF-1bidir viral vector.

Public Health Relevance

The growth of the aging population is a world-wide phenomenon. A better understanding of the decline in skeletal muscle molecular structure and function will allow more rationale interventions aimed at improving physical performance and independence in the elderly.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
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Williams, John
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Wake Forest University Health Sciences
Internal Medicine/Medicine
Schools of Medicine
United States
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Birbrair, Alexander; Zhang, Tan; Wang, Zhong-Min et al. (2014) Type-2 pericytes participate in normal and tumoral angiogenesis. Am J Physiol Cell Physiol 307:C25-38
Taylor, Jackson; Pereyra, Andrea; Zhang, Tan et al. (2014) The Cav?1a subunit regulates gene expression and suppresses myogenin in muscle progenitor cells. J Cell Biol 205:829-46
Files, D Clark; Xiao, Kunhong; Zhang, Tan et al. (2014) The posterior cricoarytenoid muscle is spared from MuRF1-mediated muscle atrophy in mice with acute lung injury. PLoS One 9:e87587
Zhang, Tan; Birbrair, Alexander; Wang, Zhong-Min et al. (2013) Troponin T nuclear localization and its role in aging skeletal muscle. Age (Dordr) 35:353-70
Mosca, Barbara; Delbono, Osvaldo; Laura Messi, Maria et al. (2013) Enhanced dihydropyridine receptor calcium channel activity restores muscle strength in JP45/CASQ1 double knockout mice. Nat Commun 4:1541
Birbrair, Alexander; Zhang, Tan; Wang, Zhong-Min et al. (2013) Skeletal muscle neural progenitor cells exhibit properties of NG2-glia. Exp Cell Res 319:45-63
Zhang, Tan; Birbrair, Alexander; Delbono, Osvaldo (2013) Nonmyofilament-associated troponin T3 nuclear and nucleolar localization sequence and leucine zipper domain mediate muscle cell apoptosis. Cytoskeleton (Hoboken) 70:134-47
Choi, Seung Jun; Shively, Carol A; Register, Thomas C et al. (2013) Force-generation capacity of single vastus lateralis muscle fibers and physical function decline with age in African green vervet monkeys. J Gerontol A Biol Sci Med Sci 68:258-67
Birbrair, Alexander; Zhang, Tan; Wang, Zhong-Min et al. (2013) Skeletal muscle pericyte subtypes differ in their differentiation potential. Stem Cell Res 10:67-84
Yasuda, Toshimichi; Delbono, Osvaldo; Wang, Zhong-Min et al. (2013) JP-45/JSRP1 variants affect skeletal muscle excitation-contraction coupling by decreasing the sensitivity of the dihydropyridine receptor. Hum Mutat 34:184-90

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