Researchers here demonstrate that mice with a larger number of mitochondrial deletion mutations exhibit a greater age-related loss of muscle fibers, a study that you might compare with past results showing reduced life span resulting from increased mitochondrial mutations. Mitochondria are the power plants of the cell, responsible for generating chemical energy store molecules, descended from symbiotic bacteria, and still bearing the leftover remnant of their original DNA. Mitochondrial dysfunction is implicated in the progression of aging and age-related disease, both from fairly high level measures of age-related changes in mitochondrial function and dynamics in specific tissues, and from an examination of mitochondrial DNA damage and its consequences. Further, differences in the composition of mitochondria correlate strongly with species life span across many types of organism: the more resistant mitochondria are to oxidative damage, the longer the life span.
The evidence to date makes a compelling argument for work on mitochondrial repair of one sort or another as the basis for a rejuvenation therapy, a way to remove this contribution to the aging process. The favored approach for the SENS Research Foundation is to insert suitably edited copies of mitochondrial genes into the cell nucleus as a form of backup, something that is, gene by gene, slowly advancing into commercial development. Deletions in mitochondrial DNA cause problems because they prevent the creation of necessary proteins required for correct function, but if the proteins are also created and supplied from the nucleus, then the expected outcome is that no harm will come from mitochondrial DNA damage.
With age, somatically derived mitochondrial DNA (mtDNA) deletion mutations arise in many tissues and species. In skeletal muscle, deletion mutations clonally accumulate along the length of individual fibers. At high intrafiber abundances, these mutations disrupt individual cell respiration - the electron transport chain (ETC) mechanisms - and are linked to the activation of apoptosis, intrafiber atrophy, breakage, and necrosis, contributing to fiber loss. This sequence of molecular and cellular events suggests a putative mechanism for the permanent loss of muscle fibers with age.
To test whether mtDNA deletion mutation accumulation is a significant contributor to the fiber loss observed in aging muscle, we pharmacologically induced deletion mutation accumulation. Beta-guanidinopropionic acid (GPA), a creatine analogue, induces mitochondrial biogenesis primarily in skeletal muscle. Previous experiments demonstrated that a 7 weeks GPA treatment of 27-month-old rats resulted in an increased incidence (3.7-fold) of ETC abnormal fibers, but did not result in measureable fiber loss. Clonally expanded mtDNA deletion mutations first appear as ETC abnormal fibers at approximately 28 months of age in the hybrid rat. We hypothesized that inducing mitochondrial biogenesis at older ages, when deletion mutation frequency is higher, would explicitly test the role of these mutations in muscle fiber loss. Four months of GPA treatment in 30-month-old rats resulted in a 12-fold increase in ETC abnormal fibers, accelerating cell death, fiber loss and fibrosis, leading to a 22% loss of muscle mass.
In muscle aging, activation of apoptosis and necrosis predominantly occurs in ETC abnormal muscle fibers. The ETC abnormality results from the focal accumulation of mtDNA deletion mutations. As GPA treatment promotes sarcopenic changes through an increase in ETC abnormal fiber abundance, treatment should also accelerate the mitochondrial genotypic changes observed with muscle aging. To test this relationship, we quantitated mtDNA deletion mutation abundances in both muscle tissue homogenates and single muscle fibers. The mtDNA deletion frequency (20%) in tissue homogenates mirrored the increased abundance of ETC abnormal fibers. Similarly, in single fibers, GPA treatment resulted in deletion mutation abundances that exceed the 90% phenotypic threshold for presentation of a respiration deficiency. These data strengthen the causal link between mtDNA deletion mutation and fiber loss and underscore the significance of latent mtDNA deletion mutations.