A common diabetes medication, metformin, which regulates blood sugar can also prevent muscle atrophy and muscle fibrosis, which can help the elderly recover faster from injury or illness.
Disuse-induced muscle fibrosis, cellular senescence, and senescence-associated secretory phenotype in older adults are alleviated during reambulation with metformin pretreatment. Summary Muscle inflammation and fibrosis underlie disuse-related complications and may contribute to poor muscle recovery in aging. Cellular senescence is an emerging link between inflammation, extracellular matrix (ECM) remodeling, and impaired muscle recovery after disuse. In rodents, metformin has been shown to prevent cellular senescence/senescence-associated secretory phenotype (SASP), inflammation and fibrosis, making it a potentially practical therapeutic solution. Therefore, the purpose of this study was to determine in older adults whether metformin monotherapy during bed rest could reduce muscle fibrosis and cellular senescence/SASP during the reambulation period. A two-arm controlled trial was used in healthy male and female older adults (n=20; BMI: <30, age: 60 years or older) randomly assigned to treatment with placebo or metformin during a two-week run-in period and 5 days of bed rest, followed by metformin withdrawal for 7 days of recovery. We found that people treated with metformin had less type I myofiber atrophy during disuse, reduced pro-inflammatory transcriptional profiles, and less muscle collagen deposition during recovery. Collagen content and myofiber size corresponded with reduction in whole muscle cellular senescence and SASP markers. Furthermore, metformin treatment reduced senescent markers of primary muscle-resident fibroadipogenic progenitors (FAPs) and promoted a shift in the fate of fibroblasts to be less similar to myofibroblasts. Together, these results suggest that metformin pretreatment enhanced extracellular matrix (ECM) remodeling after disuse in older adults by possibly altering cellular senescence and SASP in skeletal muscle and FAPs. |
Figure : Experimental scheme. A muscle biopsy was taken prior to the start of any treatment (PRE) or intervention. Participants then received placebo or metformin for 2 weeks and stopped taking their treatments 2 days before the start of bed rest. At the beginning of the first day of bed rest, a muscle biopsy was taken (DAY 1) and participants began treatments again for the next 4 days of bed rest. On the fifth day of bed rest (POST), a muscle biopsy was taken and participants stopped their treatments the night before and did not continue their treatments for the remainder of the study. After a 1-week recovery period (REC), participants returned and underwent another muscle biopsy.
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Researchers at the University of Utah Health have discovered that metformin , a common drug that has been used in the treatment of diabetes for more than half a century, has surprising applications at the cellular level. It may target "zombie-like cells ," called senescent cells , that affect muscle function. Senescent cells secrete factors associated with inflammation that may underlie fibrotic tissue, a hardening or scarring of tissues. Metformin also reduces muscle atrophy. Their findings published in Aging Cell .
"We are interested in the clinical application of this research," says Micah Drummond, Ph.D., senior author of the study and professor of physical therapy and athletic training in the College of Health. "For example, knee surgeries in the elderly are notoriously difficult to recover from. If we administered a metformin-type agent during the recovery period, could we help the muscles return to normal faster?"
Revitalizing muscle recovery
As adults age, they are more likely to fall, be hospitalized, or develop chronic illnesses, and lack of muscle use increases these risks. The research team wanted to find a therapeutic solution that could adequately address both disuse atrophy and muscle recovery.
There is an optimal level of senescent cells that are beneficial, regardless of age. In younger, healthier people, short-term senescence is required for adequate recovery from injury, and complete blocking of the senescent effect impedes the body’s efforts to heal. Typically, a younger person can recover more easily after muscle disuse without the use of an intervention such as metformin.
“In the case of aging, we know that there is immune dysfunction ,” says Drummond. "As you age, it becomes harder for your body to eliminate senescent cells and they build up. That’s one reason why recovery is much slower for older people after periods of disuse."
The antisenescent properties of metformin have been demonstrated through preclinical studies. To test the intervention in humans, the team recruited 20 healthy older adults, men and women, for a multi-week study. They had participants undergo a muscle biopsy and an MRI before the intervention, which involved five days of bed rest.
One group of 10 received metformin and the other 10 received placebo pills during a two-week run-in period, then each group continued treatment with placebo or metformin during bed rest.
After bed rest, participants received another muscle biopsy and an MRI, and then stopped the treatments. All patients completed a seven-day reambulation period followed by a final muscle biopsy.
"We saw two things in our study," Drummond says. "When participants took metformin during bed rest, they had less muscle atrophy . During the recovery period, their muscles also had less fibrosis, or excess collagen. That buildup can make it harder for the muscle to function properly."
Linking these results to senescence, the research team examined muscle biopsies from study participants. They found that participants taking metformin had fewer markers of cellular senescence.
"This is the first paper to establish a direct connection between a therapy targeting cellular senescence and improved muscle recovery after disuse in aging," says lead author Jonathan Petrocelli, Ph.D. He explains that metformin helps muscle cells better remodel and repair tissue during recovery periods after inactivity.
"Our real goal is for patients to maintain their muscle mass and function as they age, because atrophy and weakness are some of the strongest predictors of disease development and death," he says.
Drummond’s team is following up on these findings by examining combining the drug with leucine, an amino acid that promotes growth and could further speed recovery. They have already demonstrated the potency of this combination in preclinical animal studies.
"Metformin is inexpensive, effective and quite safe, so it’s exciting to see that we can use it to speed recovery in older people," adds Drummond.
In summary , treatment with metformin 2 weeks before and during disuse improved myofiber remodeling of older adults during early reambulation through alterations in collagen deposition. The effects of metformin on collagen deposition may be related to increasing anti-inflammatory transcriptional programs and reducing senescence/SASP of muscle-resident and whole-muscle FAP.
We conclude that short-term administration of metformin may be beneficial in ameliorating muscle atrophy and improving muscle recovery during short-term recovery after disuse in older adults by targeting muscle cellular senescence/SASP.
