Loss of skeletal muscle strength by ablation of the sarcoplasmic reticulum protein JP45

Delbono, Osvaldo; Xia, Jinyu; Treves, Susan; Wang, Zhongmin; Jiménez-Moreno, Ramón; Payne, Anthony M. M.; Messi, Marı́a Laura; Briguet, Alexandre; Schaerer, Florian; Nishi, Miyuki; Takeshima, Hiroshi; Zorzato, Francesco

doi:10.1073/pnas.0707389104

Cited by 37 publications

(51 citation statements)

References 47 publications

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“…12). While we have not determined the role of other triadic proteins such as JP-45 (12,55), the results of the current study offer circumstantial support that JP damage is involved in early force deficits due to EC coupling failure following the performance of eccentric contractions.…”

Section: Discussionsupporting

confidence: 38%

“…For example, JP-45 locates to the triad, binds to Cav1.1 in the T-tubule membrane and calsequestrin in the SR, appears to play a role in targeting Cav1.1 to the triad, and is required for normal EC coupling (2,3,12). On the basis of these characteristics, it is interesting to postulate that junctophilin and JP-45 damage consequent of performing eccentric contractions results in dissociation of Cav1.1 from RyR1 and then migration of Cav1.1 from the triad.…”

Section: Discussionmentioning

confidence: 99%

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Junctophilin damage contributes to early strength deficits and EC coupling failure after eccentric contractions

Corona

Balog

Doyle

et al. 2010

American Journal of Physiology-Cell Physiology

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Junctophilins (JP1 and JP2) are expressed in skeletal muscle and are the primary proteins involved in transverse (T)-tubule and sarcoplasmic reticulum (SR) membrane apposition. During the performance of eccentric contractions, the apposition of T-tubule and SR membranes may be disrupted, resulting in excitation-contraction (EC) coupling failure and thus reduced force-producing capacity. In this study, we made three primary observations: 1) through the first 3 days after the performance of 50 eccentric contractions in vivo by the left hindlimb anterior crural muscles of female mice, both JP1 and JP2 were significantly reduced by approximately 50% and 35%, respectively, while no reductions were observed after the performance of nonfatiguing concentric contractions; 2) following the performance of a repeated bout of 50 eccentric contractions in vivo, only JP1 was immediately reduced ( approximately 30%) but recovered by 3-day postinjury in tandem with the recovery of strength and EC coupling; and 3) following the performance of 10 eccentric contractions at either 15 degrees or 35 degrees C by isolated mouse extensor digitorum longus (EDL) muscle, isometric force, EC coupling, and JP1 and JP2 were only reduced after the eccentric contractions performed at 35 degrees C. Regression analysis of JP1 and JP2 content in tibialis anterior and EDL muscles from each set of experiments indicated that JP damage is significantly associated with early (0-3 days) strength deficits after performance of eccentric contractions (R = 0.49; P < 0.001). As a whole, the results of this study indicate that JP damage plays a role in early force deficits due to EC coupling failure following the performance of eccentric contractions.

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Section: Discussionsupporting

confidence: 38%

Section: Discussionmentioning

confidence: 99%

Junctophilin damage contributes to early strength deficits and EC coupling failure after eccentric contractions

Corona

Balog

Doyle

et al. 2010

American Journal of Physiology-Cell Physiology

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“…Recently, we demonstrated that increased Cavβ1a expression contributes to decreased Cav1.1 expression and muscle weakness with aging; however, the underlying mechanism is not gene transcription, because in young mice, Cav1.1 mRNA does not decline with Cavβ1a overexpression (Taylor et al ., 2009). We also demonstrated that JP45 regulates Cav1.1 expression through a mechanism independent of gene transcription (Delbono et al ., 2007, 2012). Aging skeletal muscle undergoes chronic denervation, but whether that accounts for the accumulation of nuclear TnCT remains to be examined.…”

Section: Discussionmentioning

confidence: 99%

Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1 , and enhances skeletal muscle force in aging sedentary mice

et al. 2016

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SummaryLoss of strength in human and animal models of aging can be partially attributed to a well‐recognized decrease in muscle mass; however, starting at middle‐age, the normalized force (force/muscle cross‐sectional area) in the knee extensors and single muscle fibers declines in a curvilinear manner. Strength is lost faster than muscle mass and is a more consistent risk factor for disability and death. Reduced expression of the voltage sensor Ca2+ channel α1 subunit (Cav1.1) with aging leads to excitation–contraction uncoupling, which accounts for a significant fraction of the decrease in skeletal muscle function. We recently reported that in addition to its classical cytoplasmic location, fast skeletal muscle troponin T3 (TnT3) is fragmented in aging mice, and both full‐length TnT3 (FL‐TnT3) and its carboxyl‐terminal (CT‐TnT3) fragment shuttle to the nucleus. Here, we demonstrate that it regulates transcription of Cacna1s, the gene encoding Cav1.1. Knocking down TnT3 in vivo downregulated Cav1.1. TnT3 downregulation or overexpression decreased or increased, respectively, Cacna1s promoter activity, and the effect was ablated by truncating the TnT3 nuclear localization sequence. Further, we mapped the Cacna1s promoter region and established the consensus sequence for TnT3 binding to Cacna1s promoter. Systemic administration of BDA‐410, a specific calpain inhibitor, prevented TnT3 fragmentation, and Cacna1s and Cav1.1 downregulation and improved muscle force generation in sedentary old mice.

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“…Muscle force was digitized at 4 kHz by using an AD Instruments converter. EDL tetanus was recorded in response to 350-ms pulses at 100 Hz as previously described (13). Specific force was normalized to the muscle cross-sectional area [CSA ϭ wet weight (18).…”

Section: Methodsmentioning

confidence: 99%

Remodeling of calcium handling in skeletal muscle through PGC-1α: impact on force, fatigability, and fiber type

Summermatter

Thurnheer

Santos

et al. 2012

American Journal of Physiology-Cell Physiology

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Regular endurance exercise remodels skeletal muscle, largely through the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). PGC-1α promotes fiber type switching and resistance to fatigue. Intracellular calcium levels might play a role in both adaptive phenomena, yet a role for PGC-1α in the adaptation of calcium handling in skeletal muscle remains unknown. Using mice with transgenic overexpression of PGC-1α, we now investigated the effect of PGC-1α on calcium handling in skeletal muscle. We demonstrate that PGC-1α induces a quantitative reduction in calcium release from the sarcoplasmic reticulum by diminishing the expression of calcium-releasing molecules. Concomitantly, maximal muscle force is reduced in vivo and ex vivo. In addition, PGC-1α overexpression delays calcium clearance from the myoplasm by interfering with multiple mechanisms involved in calcium removal, leading to higher myoplasmic calcium levels following contraction. During prolonged muscle activity, the delayed calcium clearance might facilitate force production in mice overexpressing PGC-1α. Our results reveal a novel role of PGC-1α in altering the contractile properties of skeletal muscle by modulating calcium handling. Importantly, our findings indicate PGC-1α to be both down- as well as upstream of calcium signaling in this tissue. Overall, our findings suggest that in the adaptation to chronic exercise, PGC-1α reduces maximal force, increases resistance to fatigue, and drives fiber type switching partly through remodeling of calcium transients, in addition to promoting slow-type myofibrillar protein expression and adequate energy supply.

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Loss of skeletal muscle strength by ablation of the sarcoplasmic reticulum protein JP45

Cited by 37 publications

References 47 publications

Junctophilin damage contributes to early strength deficits and EC coupling failure after eccentric contractions

Junctophilin damage contributes to early strength deficits and EC coupling failure after eccentric contractions

Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1 , and enhances skeletal muscle force in aging sedentary mice

Remodeling of calcium handling in skeletal muscle through PGC-1α: impact on force, fatigability, and fiber type

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