Sustained oral spermidine supplementation rescues functional and structural defects in COL6-deficient myopathic mice

COL6 (collagen type VI)-related myopathies (COL6-RM) are a distinct group of inherited muscle disorders caused by mutations of COL6 genes and characterized by early-onset muscle weakness, for which no cure is available yet. Key pathophysiological features of COL6-deficient muscles involve impaired macroautophagy/autophagy, mitochondrial dysfunction, neuromuscular junction fragmentation and myofiber apoptosis. Targeting autophagy by dietary means elicited beneficial effects in both col6a1 null (col6a1(-/-)) mice and COL6-RM patients. We previously demonstrated that one-month per os administration of the nutraceutical spermidine reactivates autophagy and ameliorates myofiber defects in col6a1(-/-) mice but does not elicit functional improvement. Here we show that a 100-day-long spermidine regimen is able to rescue muscle strength in col6a1(-/-) mice, with also a beneficial impact on mitochondria and neuromuscular junction integrity, without any noticeable side effects. Altogether, these data provide a rationale for the application of spermidine in prospective clinical trials for COL6-RM.

Automated summary

COL6-related myopathies (COL6-RM) are inherited muscle disorders caused by mutations of COL6 genes, characterized by early-onset muscle weakness. Targeting autophagy through dietary spermidine administration has shown beneficial effects in col6a1(-/-) mice and COL6-RM patients. A 100-day-long spermidine regimen rescues muscle strength in col6a1(-/-) mice and improves mitochondria and neuromuscular junction integrity, suggesting its potential application in clinical trials for COL6-RM.