The exerkine apelin reverses age-associated sarcopenia

Abstract

Sarcopenia, the degenerative loss of skeletal muscle mass, quality and strength, lacks early diagnostic tools and new therapeutic strategies to prevent the frailty-to-disability transition often responsible for the medical institutionalization of elderly individuals. Herein we report that production of the endogenous peptide apelin, induced by muscle contraction, is reduced in an age-dependent manner in humans and rodents and is positively associated with the beneficial effects of exercise in older persons. Mice deficient in either apelin or its receptor (APLNR) presented dramatic alterations in muscle function with increasing age. Various strategies that restored apelin signaling during aging further demonstrated that this peptide considerably enhanced muscle function by triggering mitochondriogenesis, autophagy and anti-inflammatory pathways in myofibers as well as enhancing the regenerative capacity by targeting muscle stem cells. Taken together, these findings revealed positive regulatory feedback between physical activity, apelin and muscle function and identified apelin both as a tool for diagnosis of early sarcopenia and as the target of an innovative pharmacological strategy to prevent age-associated muscle weakness and restore physical autonomy.

Understanding muscle regenerative decline with aging: new approaches to bring back youthfulness to aged stem cells

“…Thus, it is likely that in aged animals, the ability of exercise to induce pro‐growth and pro‐repair signals is not fully functional. Recent work suggests that this is indeed the case, at least for the exerkine apelin . The authors showed that young but not aged mice or humans increase apelin levels in response to exercise.…”

“…However, the effects of GDF11 on the muscle and its age‐related changes are still debated, with contradictory reports highlighting the need for further investigation . Another important circulatory factor affecting satellite cell function in sarcopenic muscles is the exercise‐induced myokine apelin . Apelin levels decrease with age, and studies in mice show that this has important consequences for healthspan .…”

“…Apelin levels decrease with age, and studies in mice show that this has important consequences for healthspan . A recent study revealed an association between apelin signaling and the beneficial effects of exercise, and also identified a positive effect on the regenerative capacity of aged muscle stem cells .…”

Impact and Lessons From the Lifestyle Interventions and Independence for Elders (LIFE) Clinical Trials of Physical Activity to Prevent Mobility Disability

“…In the LIFE-Pilot, the endogenous peptide apelin was positively correlated with SPPB score increases with physical activity (r 2 = 0.34; P = .0001). 28 A replication and meta-analysis of the LIFE-Pilot, LIFE, and the Health, Aging, and Body Composition cohort identified several mitochondrial DNA (mtDNA) variants that are associated with variation in walking speed. 29 Another analysis of the LIFE-Pilot and LIFE studies identified mtDNA-encoded variants that are associated with variations in systolic and mean arterial pressure.…”

Elevated H3K27ac in aged skeletal muscle leads to increase in extracellular matrix and fibrogenic conversion of muscle satellite cells

“…It is thus imperative to investigate mechanisms accounting for the age‐related muscle loss and functional decline. Changes at all levels, including gene expression, histone modification, DNA methylation, and physical changes in muscle stem cell environment, or niche, have been found to be associated with aging (Liu et al, ; Sahu et al, ; Stearns‐Reider et al, ; Su et al, ; Vinel et al, ; Zykovich et al, ). For instance, one of the studies of gene expression in aging muscle revealed that mitochondrial dysfunction is a major age‐related phenomenon and highlighted the beneficial effects of maintaining a high physical capacity in the prevention of age‐related muscle function decline (Su et al, ).…”