Circulating α-Klotho Counteracts Transforming Growth Factor-ß-Induced Sarcopenia.

α-Klotho is a longevity-related protein. Its deficiency shortens lifespan with prominent senescent phenotypes, including muscle atrophy and weakness in mice. α-Klotho has two forms: membrane α-Klotho and circulating α-Klotho (c-α-Klotho). Loss of membrane α-Klotho impairs a phosphaturic effect, thereby accelerating phosphate-induced aging. However, the mechanisms of senescence on c-α-Klotho loss remain largely unknown. Herein, with the aging of wild-type mice, c-α-Klotho declined, whereas Smad2, an intracellular transforming growth factor (TGF)-ß effector, became activated in skeletal muscle. Moreover, c-α-Klotho suppressed muscle-wasting TGF-ß molecules, including myostatin, growth and differentiation factor 11, activin, and TGF-ß1, through binding to ligands as well as type I and type II serine/threonine kinase receptors. Indeed, c-α-Klotho reversed impaired in vitro myogenesis caused by these TGF-ßs. Oral administration of Ki26894, a small-molecule inhibitor of type I receptors for these TGF-ßs, restored muscle atrophy and weakness in α-Klotho (-/-) mice and in elderly wild-type mice by suppression of activated Smad2 and up-regulated Cdkn1a (p21) transcript, a target of phosphorylated Smad2. Ki26894 also induced the slow to fast myofiber switch. These findings show c-α-Klotho's potential as a circulating inhibitor counteracting TGF-ß-induced sarcopenia. These data highlight the potential of a novel therapy involving TGF-ß blockade to prevent sarcopenia.

Becker Muscular Dystrophy Accompanied by Anti-HMGCR Antibody-positive Immune-mediated Necrotizing Myopathy.

Becker muscular dystrophy (BMD) is an X-linked neuromuscular disease characterized by progressive muscle weakness that currently has no cure. Immune-mediated necrotizing myopathy (IMNM) is a type of autoimmune inflammatory myopathy characterized by proximal muscle weakness that is treated with immunosuppressive therapy. We herein report a patient diagnosed with BMD complicated with IMNM by a pathological analysis. Notably, the patient had an elevated serum anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody level. Oral glucocorticoid and methotrexate treatment partially improved the muscle weakness with decreased levels of serum creatine kinase. An accurate diagnosis is important for therapeutic decisions in these complicated cases.

The "Ant-farm"-like Appearance of Restricted Lower Limb Vasculitis on Fluorodeoxyglucose-positron Emission Tomography.

Restricted lower limb vasculitis is a type of localized muscle vasculitis limited to the lower limbs. The usefulness of fluorodeoxyglucose-positron emission tomography (FDG-PET) for the diagnosis of this entity has not yet been reported. We herein report three patients with a fever and persistent lower limb pain. FDG-PET revealed linear and patchy FDG uptakes in their lower limbs. Combined with magnetic resonance imaging and histological findings, they were diagnosed with lower limb vasculitis. Linear and patchy FDG uptakes are considered to reflect the presence of muscle vasculitis. The characteristic "ant-farm"-like FDG-PET images can be a diagnostic clue for the currently overlooked vasculitis.

Maximal Multistage Shuttle Run Test-induced Myalgia in a Patient with Muscle Phosphorylase B Kinase Deficiency.

Muscle phosphorylase b kinase (PHK) deficiency is a rare mild metabolic disorder caused by mutations of the PHKA1 gene encoding the αM subunit of PHK. A 16-year-old boy experienced myalgia during the maximal multistage 20-m shuttle run test targeting the maximal oxygen consumption. Although an ischemic forearm exercise test was normal, a muscle biopsy revealed subsarcolemmal glycogen accumulation. He harbored a novel insertion mutation in the PHKA1 gene that resulted in premature termination of the αM subunit close to the C-terminus. Compared with previously reported cases, his reduction in PHK activity was relatively mild.