Metformin Pre-Treatment Improves ECM Remodeling and Collagen Turnover, Highlighted by CHP Use in Muscle Fibrosis
The extracellular matrix provides the structural foundation to support all our biological functioning. A healthy extracellular matrix (ECM) is marked by a balance of collagen production and degradation that allows for cellular growth, signaling, and wound repair. The regulation of ECM homeostasis is driven by a variety of resident cells that either promote the production of ECM proteins (i.e. fibroblasts synthesizing collagen) or promote the degradation of the matrix (i.e. macrophages secreting matrix metalloproteases). As we age, this balance can be skewed due to cellular senescence, which is characterized by altered secretory profiles of cytokines and ECM remodeling proteins. This study aimed to examine if metformin pretreatment could improve ECM remodeling and cellular senescence markers in aged adults during bed rest and following a short-term re-ambulation period.
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To measure the effect of metformin on myofiber atrophy and cellular senescence, muscle biopsies were taken prior to 2 weeks of metformin treatment, before and after a 5-day bed rest, and following a 1-week re-ambulation period. It was found that metformin-treated patients had increased type I myofiber CSA size after bed rest and less muscle fibrosis during recovery. This was found to be correlated with a decrease in the senescent phenotype of resident muscle cells as measured by classical senescent cell marker transcripts. Researchers were able to correlate the amount of total collagen I with the amount of remodeling collagen using Biotin-labeled Collagen Hybridizing Peptides (B-CHP) to understand how metformin treatment influenced collagen remodeling events. Given that ECM dysregulation could be associated with increased collagen deposition or increased collagen degradation, using CHP technology provided a complementary insight to the Sirius red total collagen stain that was used. Interestingly, it was found that ratio of B-CHP/Collagen I was increased in both groups, indicating increased collagen turnover after the recovery period.
In addition to the histological readouts, the group also analyzed transcriptional profiles of collagen and cellular senescence and found that metformin treatment reduced pro-inflammatory transcriptional profiles and improved collagen remodeling during recovery.
This paper showed a novel use of the Type 2 diabetes drug metformin to improve collagen remodeling and decrease the senescent cellular profile associated with bed rest. CHPs provided critical insights to the amount of collagen remodeling present in conjunction with other collagen quantification methods. Although metformin is traditionally used to lower blood glucose levels in patients with type II diabetes, this preliminary research shows its potential to be used as a powerful anti-inflammatory to prevent the senescence-associated secretory phenotype that leads to harmful degradation of the extracellular matrix. In events in which patients may be anticipating acute bed rest, these data suggest that providing a pre-treatment with metformin could prevent the adverse side effects such as muscle atrophy that can cause downstream mobility and functionality consequences. This novel solution to decrease muscular atrophy and improve muscle recovery following bed rest could aid elderly populations that may already have a dysregulated ECM due to the aging process.
Petrocelli, J. J. et al. Disuse-induced muscle fibrosis, cellular senescence, and senescence-associated secretory phenotype in older adults are alleviated during re-ambulation with metformin pre-treatment. Aging Cell 22, e13936 (2023). https://onlinelibrary.wiley.com/doi/10.1111/acel.13936
