Reversal of Age‐Related Mitochondrial Dysfunction In Vivo by Treatment with the Mitochondrially Targeted Therapeutic SS‐ 31

Abstract

In vivo mitochondrial function and energy homeostasis in skeletal muscle declines with age. The ability to reverse this dysfunction with an acute treatment would represent a new paradigm for improving skeletal muscle function in the elderly. Here we test whether the novel, mitochondrially‐targeted peptide SS‐31 restores mitochondrial energetics in aged mouse skeletal muscle in vivo. We treated young and old mice with an acute 3mg/kg dose of SS‐31 and assessed in vivo mitochondrial function and energetic state after one hour using a unique combined magnetic resonance and optical spectroscopy system. In vivo mitochondrial coupling (P/O), phosphorylation capacity, and energy state (PCr/ATP) significantly declined with age. SS‐31 significantly improved all three measures of mitochondrial energetics in skeletal muscle of aged mice, but had no observed effect in young mice. Reversal of the age‐related decline in capacity and energy state may be due to both SS‐31's antioxidant activity and a more direct facilitation of mitochondrial respiratory activity in aged muscle. These results suggest that short‐term treatment with mitochondrially targeted therapeutics may represent a new approach to reverse the effects of aging on skeletal muscle energetics. This was supported by NIH grants AG001751 and AG028455.