Competitive Inhibition of Myostatin in the Management of Sarcopenia and Muscle Wasting Disease - Implications for Primary Progressive Multiple Sclerosis
Myostatin (MSTN) is a protein from the transforming growth factor- beta (TGF-beta) category whose function, in part, is the maintenance and preservation of muscle bulk and strength. Regulation of this protein has been difficult, with variable case reports yielding ambiguous results, even with the use of follistatin, a known MSTN antagonist.
MSTN can be effectively inhibited by use of a peptide complex which competitively inhibits MSTN by noncovalent binding of the peptide complex to the C-terminal dimer. This complex maintains MSTN in an inactive latent state.
The objective is to explore a novel way of producing inhibition of MSTN through oral tolerance therapy with a selective, quantitative blend of amino complex containing fixed amounts of arginine, ornithine, and glycine. Maintaining, increasing, and restoring muscle mass in disuse atrophy associated with primary progressive multiple sclerosis (PPMS), weakness and loss of muscle bulk in myopathy, and sarcopenia in normal control subjects will be examined.
Subjects included MS patients affected by disuse atrophy (paraplegia/quadriplegia) with EDSS scores of greater than 6.0 (n= 15), patients with myopathy (n= 10), and healthy control patients ages 40-60 years who had experienced some degree of sarcopenia (n=10). Serial examinations with dynamometric strength recordings, muscle mass indices, creatinine phosphokinase (CK), and serum myostatin levels were obtained monthly over a period of 8 months. CK and MSTN levels were obtained in all patients during periods of initiation and withdrawal of the peptide. An exercise program was designed and implemented for the functional capacity of each patient.
In the disuse atrophy MS population the following was noted: no significant change in CK, a decrease in serum MSTN, improvement in muscle strength, and concomitant increase in measurable muscle bulk (10%), along with increased muscle mass index from baseline. EDSS scoring improved in 6 patients (40%) by 1-2 units over eight months. Original baseline EDSS ranged from 6.0-8.0.
The myopathic patients had an increase in CK initially followed by a precipitous decline in quantitative measurement. This was associated with a decrease in MSTN and preservation of muscle bulk. No clear change in strength recordings or muscle mass index was observed.
In healthy control subjects with sarcopenia, there was a mild rise in CK and associated decrease in serum MTSN. There was a rise in muscle strength associated with an increase in muscle bulk (23%) and muscle mass index.
Maintenance of muscle strength in neurologic disease is fraught with considerable difficulty and is ordinarily not improved by physical therapy alone. Our data suggests that use of a fixed peptide sequence of arginine, ornithine, and glycine may competitively inhibit MSTN. The adjunctive use of this form of oral tolerance therapy in clinical practice may prove quite beneficial for PPMS patients.