Restoration of Sarcoplasmic Reticulum Ca 2+ ATPase (SERCA) Activity Prevents Age-Related Muscle Atrophy and Weakness in Mice

Int J Mol Sci. 2020 Dec 22;22(1):37. doi: 10.3390/ijms22010037.

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.

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

MeSH terms

  • Age Factors
  • Aminoquinolines / administration & dosage
  • Aminoquinolines / pharmacology*
  • Animals
  • Benzamides / administration & dosage
  • Benzamides / pharmacology*
  • Enzyme Activation / drug effects
  • Injections, Intraperitoneal
  • MAP Kinase Signaling System / drug effects
  • Male
  • Mice, Inbred C57BL
  • Mitochondria, Muscle / drug effects
  • Mitochondria, Muscle / metabolism
  • Muscle Weakness / physiopathology
  • Muscle Weakness / prevention & control*
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Muscular Atrophy / metabolism
  • Muscular Atrophy / physiopathology
  • Muscular Atrophy / prevention & control*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Reactive Oxygen Species / metabolism
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism*
  • Uncoupling Protein 1 / metabolism

Substances

  • Aminoquinolines
  • Benzamides
  • CDN1163
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Reactive Oxygen Species
  • Uncoupling Protein 1
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases