Adeno-associated virus-mediated expression of myostatin propeptide improves the growth of skeletal muscle and attenuates hyperglycemia in db/db mice

Abstract

Inhibition of myostatin, a negative growth modulator for muscle, can functionally enhance muscle mass and improve glucose and fat metabolism in myostatin propeptide (MPRO) transgenic mice. This study was to investigate whether myostatin inhibition by adeno-associated virus (AAV)-mediated gene delivery of MPRO could improve muscle mass and achieve therapeutic effects on glucose regulation and lipid metabolism in the db/db mice and the mechanisms involved in that process. Eight-week-old male db/db mice were administered saline, AAV-GFP and AAV-MPRO/Fc vectors and monitored random blood glucose levels and body weight for 36 weeks. Body weight gain was not different during follow-up among the groups, but AAV-MPRO/Fc vectors resulted high level of MPRO in the blood companied by an increase in skeletal muscle mass and muscle hypertrophy. In addition, AAV-MPRO/Fc-treated db/db mice showed significantly lower blood glucose and insulin levels and significantly increased glucose tolerance and insulin sensitivity compared with the control groups (P<0.05). Moreover, these mice exhibited lower triglyceride (TG) and free fatty acid (FFA) content in the skeletal muscle, although no difference was observed in fat pad weights and serum TG and FFA levels. Finally, AAV-MPRO/Fc-treated mice had enhanced insulin signaling in the skeletal muscle. These data suggest that AAV-mediated MPRO therapy may provide an important clue for potential clinical applications to prevent type II diabetes, and these studies confirm that MPRO is a therapeutic target for type II diabetes.

RANKL inhibition improves muscle strength and insulin sensitivity and restores bone mass

“…However, our models of muscle weakness differ from the mdx mouse in that muscles were neither dystrophic nor markedly inflammatory in huRANKLTg + nor Pparb -/mice. Consistent with our data, improving glucose entry into muscle through insulin sensitivity has been shown to improve muscle strength in 2 different mouse models of aging and type 2 diabetes (Db/Db) (28,29).…”

Mss51 deletion enhances muscle metabolism and glucose homeostasis in mice

“…Eight-week-old control and Mss51-KO mice were fed an HFD for 13 weeks and then housed in individual metabolic cages and injected with 1 μCi of 1-14 C oleic acid. 14 CO 2 was collected by continuous bubbling of the air from the metabolic cage through 1N NaOH after 15, 30, 90, 180, and 240 minutes (n = 4-5 per group). The investigator conducting the experiment was blinded to the genotypes of the mice.…”

“…Genetic ablation or postnatal inhibition of myostatin is associated with increased muscle mass and decreased adipose tissue (7,8). Since skeletal muscle plays a major role in metabolic rate and insulin-mediated glucose clearance, several studies have investigated the effects of genetic and pharmacological inhibition of myostatin in mouse models of obesity and T2DM (9)(10)(11)(12)(13)(14). These studies found that lack of myostatin resulted in increased glucose uptake and insulin sensitivity in skeletal muscle of mice (15)(16)(17).…”

Electrophoretic detection of black market myostatin propeptide

“…In the past, several attempts were made to develop therapies based on myostatin propeptide for curing muscular diseases including gene therapy, antisense oligonucleotide therapy, and application of propeptide‐Fc fusion proteins 6–12 . So far, no pharmaceuticals or therapies have been approved.…”

“…5 In the past, several attempts were made to develop therapies based on myostatin propeptide for curing muscular diseases including gene therapy, antisense oligonucleotide therapy, and application of propeptide-Fc fusion proteins. [6][7][8][9][10][11][12] So far, no pharmaceuticals or therapies have been approved. The low efficacy of direct administration of myostatin propeptide was attributed to low stability of the protein in serum.…”