Complicated plasminogen system yields potential therapeutic target; Implications for aging and degenerative diseases

Skeletal muscles naturally repair themselves very efficiently after injury. But when they don’t, otherwise successful recovery following damage from overuse during exercise, surgery or trauma can be stymied. Furthermore, as we age, muscle repair slows noticeably, and in Duchenne Muscular Dystrophy and other degenerative muscle diseases, normal repair functions can’t cope with disease progression.

Researchers from the University of Illinois-Chicago (UIC) and University of Michigan report that while “skeletal muscles possess a remarkable capacity for regeneration” and self-repair, deficiency in the plasminogen activator inhibitor-1 (PAI-1) actually promotes muscle regeneration, making PAI-1 “a therapeutic target for enhancing muscle regeneration.”

Moreover, they realized that the plasminogen system interacts with the inflammatory, growth factor and other systems in a complicated manner, indicating that the plasminogen system likely has multiple functions.

For instance, Koh noted that “the inflammatory process can be a double-edged sword for muscle repair. Inflammatory cells can exacerbate an injury, but they also can produce substances that may be required for repair.  We would speculate that anti-inflammatory drugs may not be such a good idea if they’re inhibiting repair-promoting macrophage functions; they may give some short-term relief following injury, but muscle repair may not be as efficient as it would be without these drugs.”

Striking, rapid differences in strength recovery

In the current study, the investigators found that in mice lacking PAI-1, the activity of an enzyme called urokinase-type plasminogen activator (uPA) was increased in damaged muscle. The result was improved recovery of muscle function and accelerated muscle repair associated with faster increases in proteins such as the myogenic transcription factor MyoD. “In other words, we observed accelerated repair over and above what is already a naturally efficient system,” lead author Timothy J. Koh of UIC said later. 

The study, entitled “Mice deficient in plasminogen activator inhibitor-1 have improved skeletal muscle regeneration,” appears in the July issue of the American Journal of Physiology-Cell Physiology, published by the American Physiological Society. The research was conducted by Timothy J. Koh, Scott C. Bryer and Augustina M. Pucci at the University of Illinois at Chicago, and Thomas H. Sisson at the University of Michigan.

The study showed quite striking differences in how normal (wild type, or WT), PAI-1 deficient (null) and uPA null mice recovered from muscle injury. Five days after an injury, PAI-1 null mice had recouped nearly 40% of pre-injury muscle force, significantly greater than WT or uPA null mice that produced only 20% of pre-injury muscle force.

After 10 days, PAI-1 null muscle force remained significantly greater than WT (55% versus 40% of pre-injury force), with uPA null mice still showing little, if any, recovery.  By day 20, the three mouse strains’ relative muscle strength followed a similar pattern: PAI-1 null 90%, WT 75% and uPA null 35% of pre-injury force.

Koh noted that PAI levels normally increase in muscle after damage, which may limit the repair process. “So the question is,” Koh continued, “if PAI-1 limits recovery, why does it increase after injury?  It may be that PAI-1 is a multifunctional molecule and does some things that we haven’t yet identified and measured.” Indeed the paper says that “in addition to influencing myogenesis directly, PAI-1 may modulate regeneration by regulating the inflammatory response (and) may also modulate muscle regeneration through the regulation of extracellular matrix turnover (or) by regulating the bioactivity of a variety of growth factors.”

Role of macrophages likely important

Confirming earlier studies indicating a critical role of the plasminogen system in muscle repair, the UIC-Michigan team reported that deficiency in uPA pretty much eliminated muscle regeneration after injury.  Muscles in animals without uPA showed no evidence of repair and little accumulation of macrophages, roaming cells that protect the body against foreign substances.  PAI-1 deficient muscles showed “increased macrophage accumulation (and) the extent of macrophage accumulation correlated with both the clearance of (damaged) protein after injury and the efficiency of regeneration,” according to the report.

Macrophage accumulation was impaired in injured muscle of uPA null mice and increased in PAI-1 null mice, compared to WT mice.  At days three and five, macrophage accumulation in WT muscle was significantly greater than in uninjured control levels, while macrophage accumulation in PAI-1 null muscle was greater than in WT.  Macrophage accumulation for uPA null mice was almost absent and significantly less than in WT mice.

Implications for aging and muscle diseases, and next steps

Koh noted that researchers are studying the role of the plasminogen system in repair of different tissues, including liver, lungs and the heart.  The plasminogen system may be critical for efficient repair of many tissues and for minimizing scar formation.

Koh noted the following specific areas of interest:

·         PAI-1 levels appear to increase with aging, and may explain, in part, the loss of repair capacity as we age.  Koh plans to see whether manipulating PAI-1 levels can restore muscle repair in old muscles.

·         PAI-1 levels also appear to be higher in muscle diseases like Duchenne Muscular Dystrophy.  In such diseases, muscle repair processes can’t keep up with the degeneration caused by the disease.  The plasminogen system may represent a therapeutic target for improving muscle function in these instances.

·         The plasminogen system likely has multiple roles in muscle repair.  Understanding how the plasminogen system works in skeletal muscle may give some clues to improving repair of different tissues, especially heart, which is similar in many ways to skeletal muscle.

Source and funding

The study, entitled “Mice deficient in plasminogen activator inhibitor-1 have improved skeletal muscle regeneration,” appears in the July issue of the American Journal of Physiology-Cell Physiology, published by the American Physiological Society. The research was conducted by Timothy J. Koh, Scott C. Bryer and Augustina M. Pucci, Department of Movement Sciences at the University of Illinois at Chicago, and Thomas H. Sisson, Department of Internal Medicine at the University of Michigan, Ann Arbor.