The levels of BNIP3, a protein implicated in muscle fiber atrophy and increased autophagy — two features of late-onset Pompe disease (LOPD) — are increased in muscle samples from LOPD patients relative to healthy people, a small study shows.
Autophagy is a pathway by which cells break down damaged or unnecessary proteins and other cellular components.
While this difference failed to reach statistical significance — likely due to the small number of samples — boosting BNIP3 production in lab-grown, healthy muscle progenitor cells led to the generation of smaller muscle fibers (atrophy).
These findings suggest that BNIP3 has an important role in the abnormal autophagic processes and muscle atrophy seen in LOPD, thereby representing a potential therapeutic target for this disease, the researchers noted.
More studies are needed to confirm these findings and to assess the therapeutic effects of molecules known to suppress BNIP3 in animal models of LOPD.
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The study, “BNIP3 Is Involved in Muscle Fiber Atrophy in Late-Onset Pompe Disease Patients,” was published in The American Journal of Pathology.
LOPD, which can emerge in childhood or adulthood, is a genetic condition caused by the toxic buildup of a complex sugar molecule called glycogen in several tissues, such as muscle, due to deficient levels of the acid-alpha glucosidase enzyme. This typically leads to muscle weakness and respiratory problems.
Muscle biopsies from people with LOPD show accumulation of glycogen and autophagy-related vesicles, called autophagic vacuoles, as well as atrophied, or shrunken, muscle fibers.
Autophagic vacuoles are thought to accumulate in LOPD muscle tissue due to an impaired autophagy pathway, which has been implicated in muscle atrophy.
“Uncovering the molecules involved in the muscle degeneration process could contribute to the identification of new targets for therapy,” the researchers wrote.
Now, a team of researchers in Spain and Germany identified BNIP3, a protein involved in autophagy and muscle atrophy, as an important contributor to the muscle atrophy process in LOPD.
They analyzed muscle biopsies from 12 people with LOPD and muscle cells from four LOPD patients. Samples from patients with dermatomyositis (an inflammatory muscle disease) were used as positive controls and those of healthy people as negative controls.
The team first found that, in LOPD patients, muscle fibers containing autophagic vacuoles were 12.2% thinner relative to those without vacuoles and that a higher number of vacuoles was significantly associated with reduced muscle fiber diameter.
Notably, more than 90% of muscle fibers with autophagic vacuoles were positive for BNIP3 in LOPD patients, and “all BNIP3-positive fibers were vacuolated and atrophic, which suggests a link between the [production] of this molecule, induction of autophagy, and progressive muscle fiber atrophy,” the researchers wrote.
BNIP3 levels also were increased in muscle biopsies and lab-grown myoblast-derived myotubes from people with LOPD when compared with those from healthy people. However, this difference did not reach statistical significance, possibly due to the small number of samples.
Myoblasts are the precursors of muscle cells; myotubes are immature forms of muscle fiber.
Also, lab-grown myoblasts from LOPD patients matured into significantly smaller myotubes than those from healthy individuals.
Notably, increasing the production of BNIP3 in lab-grown healthy myoblasts also resulted in the generation of significantly smaller myotubes, “suggesting that BNIP3 [overproduction] induced myotube atrophy,” the researchers wrote.
Further analyses suggested a signaling cascade that starts with the suppression of the AKT/mTOR pathway that allows the activation of the autophagy-promoter ULK1 and increases the production of BNIP3, likely perpetuating autophagy and leading to progressive muscle fiber atrophy.
These findings strongly suggest that “BNIP3 has a prominent role in autophagy and muscle fiber atrophy in LOPD patients,” and that “therapeutic modulation of BNIP3 activity could be a potential complementary new therapeutic strategy to be tested in Pompe disease,” the team wrote.
Notably, a compound called misoprostol previously was shown to suppress BNIP3 production.
More studies are needed to test whether misoprostol, or other similar treatments, could suppress “BNIP3 activity in muscle fibers to reduce autophagy and atrophy in cell or animal models of Pompe disease,” the researchers concluded.
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