Restoration of Sarcoplasmic Reticulum Ca2+ ATPase (SERCA) Activity Prevents Age-Related Muscle Atrophy and Weakness in Mice

Qaisar, Rizwan; Pharaoh, Gavin; Bhaskaran, Shylesh; Xu, Hongyang; Ranjit, Rojina; Bian, Jan; Ahn, Bumsoo; Georgescu, Constantin; Wren, Jonathan D.; Van Remmen, Holly

doi:10.3390/ijms22010037

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Restoration of Sarcoplasmic Reticulum Ca²⁺ ATPase (SERCA) Activity Prevents Age-Related Muscle Atrophy and Weakness in Mice

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Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA

Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, UAE

Division of Genomics and Data Sciences, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA

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Oklahoma City VA Medical Center, Oklahoma City, OK 73104, USA

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2021, 22(1), 37; https://doi.org/10.3390/ijms22010037

Received: 25 November 2020 / Revised: 18 December 2020 / Accepted: 19 December 2020 / Published: 22 December 2020

(This article belongs to the Special Issue Muscular Structure, Physiology and Metabolism)

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Abstract

Sarcopenia has a significant negative impact on healthspan in the elderly and effective pharmacologic interventions remain elusive. We have previously demonstrated that sarcopenia is associated with reduced activity of the sarcoplasmic reticulum Ca²⁺ ATPase (SERCA) pump. We asked whether restoring SERCA activity using pharmacologic activation in aging mice could mitigate the sarcopenia phenotype. We treated 16-month male C57BL/6J mice with vehicle or CDN1163, an allosteric SERCA activator, for 10 months. At 26 months, maximal SERCA activity was reduced 41% in gastrocnemius muscle in vehicle-treated mice but maintained in old CDN1163 treated mice. Reductions in gastrocnemius mass (9%) and in vitro specific force generation in extensor digitorum longus muscle (11%) in 26 versus 16-month-old wild-type mice were also reversed by CDN1163. CDN1163 administered by intra-peritoneal injection also prevented the increase in mitochondrial ROS production in gastrocnemius muscles of aged mice. Transcriptomic analysis revealed that these effects are at least in part mediated by enhanced cellular energetics by activation of PGC1-α, UCP1, HSF1, and APMK and increased regenerative capacity by suppression of MEF2C and p38 MAPK signaling. Together, these exciting findings are the first to support that pharmacological targeting of SERCA can be an effective therapy to counter age-related muscle dysfunction. View Full-Text

Keywords: skeletal muscle; sarcoplasmic reticulum calcium-transporting ATPase; sarcopenia

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MDPI and ACS Style

Qaisar, R.; Pharaoh, G.; Bhaskaran, S.; Xu, H.; Ranjit, R.; Bian, J.; Ahn, B.; Georgescu, C.; Wren, J.D.; Van Remmen, H. Restoration of Sarcoplasmic Reticulum Ca²⁺ ATPase (SERCA) Activity Prevents Age-Related Muscle Atrophy and Weakness in Mice. Int. J. Mol. Sci. 2021, 22, 37. https://doi.org/10.3390/ijms22010037

AMA Style

Qaisar R, Pharaoh G, Bhaskaran S, Xu H, Ranjit R, Bian J, Ahn B, Georgescu C, Wren JD, Van Remmen H. Restoration of Sarcoplasmic Reticulum Ca²⁺ ATPase (SERCA) Activity Prevents Age-Related Muscle Atrophy and Weakness in Mice. International Journal of Molecular Sciences. 2021; 22(1):37. https://doi.org/10.3390/ijms22010037

Chicago/Turabian Style

Qaisar, Rizwan, Gavin Pharaoh, Shylesh Bhaskaran, Hongyang Xu, Rojina Ranjit, Jan Bian, Bumsoo Ahn, Constantin Georgescu, Jonathan D. Wren, and Holly Van Remmen. 2021. "Restoration of Sarcoplasmic Reticulum Ca²⁺ ATPase (SERCA) Activity Prevents Age-Related Muscle Atrophy and Weakness in Mice" International Journal of Molecular Sciences 22, no. 1: 37. https://doi.org/10.3390/ijms22010037

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Restoration of Sarcoplasmic Reticulum Ca²⁺ ATPase (SERCA) Activity Prevents Age-Related Muscle Atrophy and Weakness in Mice

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