Loss of adult skeletal muscle stem cells drives age-related neuromuscular junction degeneration.

Neuromuscular junction degeneration is a prominent aspect of sarcopenia, the age-associated loss of skeletal muscle integrity. Previously, we showed that muscle stem cells activate and contribute to mouse neuromuscular junction regeneration in response to denervation (Liu et al., 2015). Here, we examined gene expression profiles and neuromuscular junction integrity in aged mouse muscles, and unexpectedly found limited denervation despite a high level of degenerated neuromuscular junctions. Instead, degenerated neuromuscular junctions were associated with reduced contribution from muscle stem cells. Indeed, muscle stem cell depletion was sufficient to induce neuromuscular junction degeneration at a younger age. Conversely, prevention of muscle stem cell and derived myonuclei loss was associated with attenuation of age-related neuromuscular junction degeneration, muscle atrophy, and the promotion of aged muscle force generation. Our observations demonstrate that deficiencies in muscle stem cell fate and post-synaptic myogenesis provide a cellular basis for age-related neuromuscular junction degeneration and associated skeletal muscle decline.

Hepatic metabisulfite sensitivity in a patient with sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis is an uncommon chronic cholestatic liver disease with a poor prognosis in symptomatic cases. Genetic and immunologic alterations have been identified, and many possible etiologies have been entertained. Most treatments have limited benefit, and primary sclerosing cholangitis is a common cause for liver transplantation. OBJECTIVE: To describe a patient with documented primary sclerosing cholangitis associated with chronic ulcerative colitis, who developed hepatic toxicity following ingestion of metabisulfite. RESULTS: A placebo-controlled oral challenge suggested metabisulfite hypersensitivity with liver toxicity. He was treated with cobalamin (to prevent sulfite toxicity), low-sulfite diet, steroids, and antibiotics and has had an unusually benign course for 19 years. CONCLUSIONS: The hypersensitivity to oral metabisulfite in our patient appeared to be a significant trigger to flare-ups of his disease. Controlling the response to metabisulfite (along with recurrent antibiotic and steroid therapy) may have contributed significantly to the remarkably good outcome in this patient.