Disuse-induced muscle fibrosis, cellular senescence, and senescence-associated secretory phenotype in older adults are alleviated during re-ambulation with metformin pre-treatment.

Muscle inflammation and fibrosis underlie disuse-related complications and may contribute to impaired muscle recovery in aging. Cellular senescence is an emerging link between inflammation, extracellular matrix (ECM) remodeling and poor muscle recovery after disuse. In rodents, metformin has been shown to prevent cellular senescence/senescent associated secretory phenotype (SASP), inflammation, and fibrosis making it a potentially practical therapeutic solution. Thus, the purpose of this study was to determine in older adults if metformin monotherapy during bed rest could reduce muscle fibrosis and cellular senescence/SASP during the re-ambulation period. A two-arm controlled trial was utilized in healthy male and female older adults (n = 20; BMI: <30, age: 60 years+) randomized into either placebo or metformin treatment during a two-week run-in and 5 days of bedrest followed by metformin withdrawal during 7 days of recovery. We found that metformin-treated individuals had less type-I myofiber atrophy during disuse, reduced pro-inflammatory transcriptional profiles, and lower muscle collagen deposition during recovery. Collagen content and myofiber size corresponded to reduced whole muscle cellular senescence and SASP markers. Moreover, metformin treatment reduced primary muscle resident fibro-adipogenic progenitors (FAPs) senescent markers and promoted a shift in fibroblast fate to be less myofibroblast-like. Together, these results suggest that metformin pre-treatment improved ECM remodeling after disuse in older adults by possibly altering cellular senescence and SASP in skeletal muscle and in FAPs.

Mechanisms of Aerobic Exercise Impairment in Diabetes: A Narrative Review.

The prevalence of diabetes in the United States and globally has been rapidly increasing over the last several decades. There are now estimated to be 30.3 million people in the United States and 422 million people worldwide with diabetes. Diabetes is associated with a greatly increased risk of cardiovascular mortality, which is the leading cause of death in adults with diabetes. While exercise training is a cornerstone of diabetes treatment, people with diabetes have well-described aerobic exercise impairments that may create an additional diabetes-specific barrier to adding regular exercise to their lifestyle. Physiologic mechanisms linked to exercise impairment in diabetes include insulin resistance, cardiac abnormalities, mitochondrial function, and the ability of the body to supply oxygen. In this paper, we highlight the abnormalities of exercise in type 2 diabetes as well as potential therapeutic approaches.