Increased Skeletal Muscle Fiber Cross-Sectional Area, Muscle Phenotype Shift, and Altered Insulin Signaling in Rat Hindlimb Muscles in a Prenatally Androgenized Rat Model for Polycystic Ovary Syndrome.

Auryana Dechick,Jack Lee,Diana L Speelman,Rebecca Hetz

doi:10.3390/ijms21217918

Abstract

Women with polycystic ovary syndrome (PCOS) are reported to have greater lean mass and insulin resistance. To examine muscular changes in a prenatally androgenized (PNA) rat model for PCOS, Sprague–Dawley rats were exposed to 5 mg testosterone or vehicle daily on gestational days 16–19. At 15 weeks of age, endurance on a rota-rod treadmill was measured. At 16 weeks of age, fasting blood glucose and insulin, hindlimb skeletal muscle mass, muscle fiber cross-sectional area (CSA) and composition, and intra- and peri-muscular lipid droplets were examined. Expression of mitochondrial marker ATP synthase and insulin signaling proteins were also investigated. Compared with controls, PNA female rats demonstrated greater total body and hindlimb muscle weights, greater muscle fiber CSA, and trending reduced time on the rota-rod. An increase in fibers co-expressing the slow and fast isoforms of myosin (90 vs. 86%, p < 0.05) and greater expression of ATP synthase (6-fold, p < 0.005) were observed in the gastrocnemius (GN) muscle. More lipid content was observed in GN and tibialis anterior (TA) muscles. PNA rats had elevated fasting serum insulin (1.9 vs. 1.2 ng/mL, p < 0.005) but comparable fasting glucose. Expression of total and Ser636/9-phosphorylated IRS1 were altered in PNA rat hindlimb muscles. Together, skeletal muscle alterations in hindlimb muscles of a PNA rat model for PCOS may represent consequences of, or adaptations to, insulin resistance in this model.

Highlights

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women, affecting female reproductive, metabolic, and psychological health from puberty to menopause and beyond [1,2,3].Evidence supports a key role for elevated levels of androgens in the pathogenesis of PCOS [4,5,6,7,8,9,10,11], which can influence the function of various tissues in the body, including skeletal muscle
This is the first study to demonstrate altered hindlimb skeletal muscle fiber cross-sectional area and composition, in conjunction with changes in insulin signaling pathway protein expression, in a Prenatally androgenized (PNA) rat model for PCOS
We examined the expression of total and Ser636/9 -phosphorylated IRS1 and found an apparent decrease in the ratio of the phosphorylated form relative to total IRS1 in gastrocnemius and tibialis anterior muscles; together with increased lipid content, these findings are consistent with insulin resistance in these muscles

Summary

Introduction

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women, affecting female reproductive, metabolic, and psychological health from puberty to menopause and beyond [1,2,3].Evidence supports a key role for elevated levels of androgens in the pathogenesis of PCOS [4,5,6,7,8,9,10,11], which can influence the function of various tissues in the body, including skeletal muscle. Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women, affecting female reproductive, metabolic, and psychological health from puberty to menopause and beyond [1,2,3]. Women with PCOS are reported to have increased lean mass [15,16,17], greater muscle strength [18,19], and enhanced muscle strength after progressive resistance training [20], suggesting a relationship between elevated androgen levels and muscle structure or function in these women. Muscle size is reported to positively correlate with serum androgen levels in women with PCOS [18,21,22], some did not find a relationship between lean mass and androgen levels [15,16].

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