A torn ACL is a common knee injury suffered by one in 50 male athletes and one in 29 female athletes, on average. “Despite improvements in surgical techniques to reconstruct torn ACLs, muscle weakness remains a major limiting factor in returning athletes to their preinjury level of performance. Even after rehabilitation, many patients have muscles that are 30 to 40 percent weaker when they return to sports compared to their pre-surgery strength,” says Christopher Mendias, PhD, ATC, an associate scientist in the Arthritis and Tissue Degeneration Program at HSS. “Inactivity during rest and recovery, which is needed to protect a surgically reconstructed ligament, promotes muscle weakness. Surgery can also induce local inflammation, which encourages muscle protein breakdown.”

Dr. Mendias, the first author on the paper published May 26 in the American Journal of Sports Medicine, began working on the study when he was at the University of Michigan. After he moved to HSS, the study continued as a collaborative initiative between the two institutions.

The researchers obtained an investigational new drug exemption from the US Food & Drug Administration (FDA) to use HGH (somatropin) in the study. The drug is available only by prescription for treating growth hormone deficiency syndromes and cannot be used off-label without FDA approval. The side effects of the drug include carpal tunnel syndrome from fluid retention, altered blood sugar levels, joint aches, muscle pains, bruising at the injection site, tingling sensations and headaches.

As the biggest risk with HGH is the development of type 2 diabetes, a condition that involves elevated blood sugar levels, patients who already had diabetes were excluded from participating in the study. Researchers also excluded collegiate, professional or elite athletes from participating in the study, since HGH is currently listed as a banned substance by the World Anti-Doping Agency (WADA), the National Collegiate Athletic Association and other professional sports organizations.

Nineteen male athletes ages 18 to 35 with ACL tears who were scheduled to undergo ACL reconstruction at the University of Michigan were randomly assigned to self-inject HGH or a saline solution under the skin in the abdominal area twice daily over six weeks, starting one week before ACL reconstruction. The assignment to groups was blinded to patients and study investigators.

Researchers measured knee muscle strength and volume and patient-reported outcomes, including pain, quality of life, symptoms and sport and recreation function. They also analyzed biomarkers in blood samples two weeks before surgery and at follow-up visits over six months after ACL reconstruction and compared the results with those from blood samples provided by healthy patients without ACL tears at HSS.

Patients who were treated with HGH had 29 percent higher knee extension strength than patients in the placebo group, a statistically significant improvement. The use of HGH was not associated with changes in muscle volume or patient-reported outcome scores and had no effect on blood sugar levels. The treatments were well tolerated with no differences in adverse events between the HGH group and the placebo group.

Blood analyses showed that patients who had HGH treatments had a 2.1-fold increase in circulating insulin-like growth factor 1 (IGF1), a protein that plays an important role in muscle growth, and a 36 percent lower level of MMP3, an enzyme released by joint membranes during inflammation and an indirect marker of cartilage degradation.

“We observed a consistent reduction in MMP3 in the human growth hormone group from the first through the 12^th post-operative weeks,” says Dr. Mendias. “This finding suggests a potential protective effect of human growth hormone after ACL reconstruction and that we should look more closely at its potential for cartilage healing in further studies.”

Although WADA and other sports agencies have banned the use of HGH by athletes, researchers believe that athletes could petition for a Therapeutic Use Exception, which would allow it for a medically appropriate reason. “We think using human growth hormone to prevent loss of muscle strength after ACL reconstruction would meet the therapeutic use exception guidelines,” says Dr. Mendias. “Treatment occurs during a time when athletes are not playing due to their injuries. The goal is to prevent muscle weakness, not make athletes stronger than they were before their injuries. Any small performance-enhancing effects of human growth hormone seem to wear off quickly after stopping the medication.”

People who experience an ACL tear are nine times more likely to develop painful, degenerative osteoarthritis later in life. “Preventing the loss of strength after ACL reconstruction with human growth hormone may help prevent the development or lessen the severity of osteoarthritis in the future,” says Dr. Mendias.

“We are encouraged by the results of our pilot study, but before making clinical recommendations, we need to do larger studies testing higher doses of human growth hormone in both males and females,” Dr. Mendias says. “We would also need to petition the FDA to approve the addition of orthopedic injuries as an on-label indication for the drug.”

The study was supported by funding provided by the Mark Cuban Foundation and the National Institute of Arthritis and Musculoskeletal and Skin Disorders, a branch of the National Institutes of Health.

Tendons connect muscles to bone, allowing the body to move. They respond and adapt to the demands of specific activities such as walking, running or playing sports. For example, leg tendons become more spring-like in basketball players, allowing them to jump higher and with more explosive force. Tendon injuries such as Achilles tendon rupture can occur through overuse or repetitive strain and are common among athletes.

“Ruptured tendons can be catastrophic. About 30 percent of athletes with an Achilles tendon rupture are not able to return to play, and those who do return regain about 75 percent of their pre-injury ability,” said senior author Christopher Mendias, PhD, ATC, an associate scientist in the Orthopaedic Soft Tissue Research Program at HSS. “There has been a lot of discussion in the NBA and other professional sports leagues about the recent increase in Achilles tendon ruptures and tendon injuries. We are also seeing an increase in tendon ruptures in the general population.”

In the basic science study, published September 19, 2019, in The FASEB Journal, the HSS researchers used advanced genetics techniques to remove the IGF1 gene in cells and then monitored tendon growth. They found that without IGF1, tendons were smaller and didn’t adapt like they normally would.

Next, the researchers added IGF1 to tendon cells in culture to study precisely how IGF1 affected the cells’ growth processes. “Two of the ways that IGF1 affected tendon cells was through increasing cell division and stimulating the synthesis of new proteins.,” said first author Nathaniel Disser, BS, a research fellow at HSS. Making new protein, such as collagen, is an important process the body uses to form tendons and other connective tissues.

In humans, growth hormone drives childhood growth and helps preserve tissues throughout adult life by maintaining adequate IGF1 levels. Human growth hormone (somatropin) is already available by prescription for treating children with growth failure due to growth hormone deficiency or adults with growth hormone deficiency. There is also another available drug called mecasermin (Increlex), which is a form of IGF1. It is used to treat children with a severe growth hormone deficiency, such as the absence of a gene to produce growth hormone.

“Overall, our study has identified that IGF1 plays an essential role in tendon growth and paves the way for future research to test whether targeting IGF1 is useful for treating painful and debilitating tendon injuries,” Dr. Mendias said. “Clinical trials are required before drawing conclusions about the ability of human growth hormone to repair tendon injuries better than is possible today.”

Dr. Mendias and colleagues are also currently completing a clinical trial testing the ability of human growth hormone to increase IGF1 levels to see whether that may prevent muscle atrophy in people recovering from anterior cruciate ligament (ACL) tears.

"Satellite" stem cells in the rotator cuff are more likely to develop into fat cells and less likely to develop into muscle cells, compared to calf muscle satellite cells, according to the experimental study by Christopher L. Mendias, PhD, ATC, and colleagues of the University of Michigan Medical School, Ann Arbor, and the Hospital for Special Surgery, New York. The researchers write, "There appears to be a cellular and genetic basis behind the generally poor rates of rotator cuff muscle healing."

'Satellite Cells' May Form More Fat Than Muscle after Rotator Cuff Tears

The researchers performed a series of experiments using muscle cells from mice to evaluate the characteristics of a type of stem cells called satellite cells. Stem cells are specialized cells with the potential to develop into different types of cells. Satellite cells, located between muscle fibers, play an essential role in repair after muscle injuries.

Tears of the shoulder rotator cuff are a common problem. Especially in chronic tears, deposits of fat often develop, contributing to weakening and atrophy of the rotator cuff muscles. This fatty infiltration can continue even after successful rotator cuff repair surgery.

Dr. Mendias and colleagues created cultures of satellite cells isolated from mouse rotator cuff and calf muscles. "Clinically, we know that the rotator cuff is one of the most difficult muscle groups to rehabilitate after injury, and this is thought to occur due to the extensive fat that accumulates in the muscle in patients with chronic tears," says lead author Manuel Schubert, MD, MS, chief resident in orthopaedic surgery at the University of Michigan. "We thought there might be a genetic basis to explain why the rotator cuff accumulates fat after injury, and the specialized transgenic model we used in this study allowed us to precisely test this." 

Compared to the calf muscle satellite cells, satellite cells from the rotator cuff developed into 23 percent fewer muscle cells, and they showed an 87 percent decrease in a "marker" for muscle formation. The rotator cuff satellite cells also had a four- to 65-fold increase in markers of genes involved in fat cell generation (adipogenesis).

DNA-level (epigenetic) studies identified hundreds of differences in gene activation between satellite cells from rotator cuff versus calf muscles. The affected genes were involved in pathways related to fat metabolism and adipogenesis, suggesting the muscle stem cells from the rotator cuff are programmed to more easily become fat cells.

Building on previous research, the new study shows increased "adipogenic differentiation capacity" of rotator cuff satellite cells. Increased potential to develop into fat cells - and decreased potential to develop into muscle cells - may be an important explanation for the high rate of fatty infiltration in muscles of patients with chronic rotator cuff tears, even after rotator cuff surgery.

The study also has potential therapeutic findings. "Satellite cells can be isolated from other muscle groups with relative ease." says Dr. Mendias, an Associate Scientist at the Hospital for Special Surgery and an Adjunct Associate Professor at the University of Michigan. "While further studies are necessary, it is possible that a patient's own stem cells from a muscle that heals well, like the calf, could be transplanted to the rotator cuff muscle at the time of surgical repair. These transplanted cells might be better able to regenerate the chronically damaged muscle than the resident stem cells."

Dr. Mendias spoke about his current research on human growth hormones (HGH) and how it could improve tissue healing in athletes.

"It's just the name - human growth hormone. It sounds like that's going to make you bigger and stronger, and it's true when you're a kid. As an adult, the data doesn't support that the growth hormone doesn't actually make you that much stronger," said Dr. Mendias.

According to the segment, Dr. Mendias and his team are investigating if HGH injections could help ACL surgery patients have a speedy recovery.

"We're trying to use human growth hormone to see if we can actually protect against muscle atrophy after an ACL tear. The primary goal is to help prevent years of osteoarthritis. Because patients lose a lot of muscle strength during that period right after surgery. If we could protect against some of the loss, then as patients go through rehabilitation then they'll be able to regain their strength back to what it was before they had the injury," Dr. Mendias explained.

Watch the full segment at espn.com [subscription required]. This episode was released on ESPN+ on July 16, 2018.

The goals of the study, which is now enrolling patients, is to find biomarkers correlated with the development of osteoarthritis of the joint after surgery to fix traumatic tears of the meniscus. This horseshoe-shaped layer of cartilage cushions the bones of the knee during weight-bearing activities like running and jumping.

More than one million Americans annually undergo meniscal surgery, making it among the most common orthopedic procedures performed in the United States. The injuries generally occur in young athletes who experience violent trauma to the knee, although older people can suffer them without such trauma, as well. However, patients who undergo the procedure often develop osteoarthritis of the joint—a painful, degenerative condition that to date has no cure or particularly effective treatment.

"The bottom line is, this is a very common orthopedic surgery and the results are not very good," said David W. Altchek, MD, sports medicine surgeon and co-chief emeritus of HSS Sports Medicine, and medical director for the New York Mets. "It seems like the surgery makes a small number of people better, some have an indifferent response and, unfortunately, a significant number of people get worse."

"We don’t really know much about the biology of how the meniscus heals. We kind of let pain be the guide," added Christopher Mendias, PhD, ATC, associate scientist at HSS, who is helping conduct the study. "We want to be able to say, 'Is it healing well, and is there a correlation between doing poorly clinically and elevated levels of pro-inflammatory biomarkers or that we can detect with advanced imaging?'"

The HSS study will have several components. Drs. Altchek, Mendias and their colleagues will take samples of synovial fluid--a viscous substance that lubricates joints--from 28 patients (14 men and 14 women) aged 18 to 45 undergoing a procedure called partial meniscectomy in which surgeons shave away frayed pieces of the cartilage. Those samples will be screened for the presence of proteins associated with inflammation, molecules such as interleukin 1 beta, which is known to play a role in osteoarthritis, as well as other previously unidentified substances.

The researchers also will use an advanced form of magnetic resonance imaging to track meniscal healing over time, and will match that information with the biomarker activity to look for patterns of protein activity that predict either successful healing or poor outcomes.  

"This whole idea of precision medicine is just kind of catching on in orthopedics now," Dr. Mendias said. Ideally, a biomarker panel could help surgeons determine which patients will be most likely to benefit from particular meniscal procedures, and what kind of rehabilitation--and even prehabilitation--routine they should undergo. "It could also help us identify therapies to block those inflammatory molecules and reduce the risks of osteoarthritis later in life," he said.

"The hypothesis is that there is a degenerative effect afterward, as a result of the injury or the surgery, or both—and that biologic therapy might slow that down," Dr. Altchek said. He added that there is "a tremendous amount of excitement" in the field of orthopedics about new biologic therapies, including platelet rich plasma and stem cells, that are now being used to treat tendon injuries and certain other ailments. Whether they might work to treat or even prevent the development of osteoarthritis after knee surgery is unclear. "This project is an important step in the direction" of answering that question, he said.

Scott A. Rodeo, MD, sports medicine surgeon, co-chief emeritus of HSS Sports Medicine, and co-director of the Tissue Engineering, Regeneration, and Repair Program, will be contributing patients to the study.

"A common clinical observation is that there is tremendous variability in the rate and risk of progressive degenerative changes in patients undergoing surgery for meniscus injury," said Dr. Rodeo, who also is head team physician for the New York Giants. "Some patients will do well for decades with no further problems, while there is a subset of patients who develop relatively rapid progression of degenerative changes. In addition to biomechanical factors, it is likely that the ‘biologic milieu’ in the joint is a major factor accounting for these discrepant outcomes. In this study we will characterize inflammatory mediators, matrix degrading enzymes, and a host of other cytokines that likely play an important role in joint homeostasis. Such information will not only help us gain a better understanding of the underlying mechanism of joint degeneration in patients with meniscus injury, but, importantly, may suggest therapeutic targets to allow development of innovative treatments."

Other HSS physicians involved include HSS sports medicine surgeons Answorth A. Allen, MD, New York Knicks team physician; and Riley J. Williams III, MD, medical director of the Brooklyn Nets.

If you have a meniscus tear and are interested in the study, or would like to serve as a healthy control subject, please contact Daniel Edon (edond@hss.edu).