Characterizing skeletal muscle dysfunction in women with polycystic ovary syndrome

Abstract

Polycystic ovary syndrome (PCOS) is the most common endocrine condition affecting women. It has traditionally been viewed as a primarily reproductive disorder; however, it is increasingly recognized as a lifelong metabolic disease. Women with PCOS are at increased risk of insulin resistance (IR), type 2 diabetes mellitus, non-alcoholic fatty liver disease and cardiovascular disease. Although not currently a diagnostic criterion, IR is a cardinal pathophysiological feature and highly prevalent in women with PCOS. Androgens play a bidirectional role in the pathogenesis of IR, and there is a complex interplay between IR and androgen excess in women with PCOS. Skeletal muscle has a key role in maintaining metabolic homeostasis and is also a metabolic target organ of androgen action. Skeletal muscle is the organ responsible for the majority of insulin-mediated glucose disposal. There is growing interest in the relationship between skeletal muscle, androgen excess and mitochondrial dysfunction in the pathogenesis of metabolic disease in PCOS. Molecular mechanisms underpinning defects in skeletal muscle dysfunction in PCOS remain to be elucidated, but may represent promising targets for future therapeutic intervention. In this review, we aim to explore the role of skeletal muscle in metabolism, focusing particularly on perturbations in skeletal muscle specific to PCOS as observed in recent molecular and in vivo human studies. We review the possible role of androgens in the pathophysiology of skeletal muscle abnormalities in PCOS, and identify knowledge gaps, areas for future research and potential therapeutic implications. Despite increasing interest in the area of skeletal muscle dysfunction in women with PCOS, significant challenges and unanswered questions remain, and going forward, novel innovative approaches will be required to dissect the underlying mechanisms.

AMPK Activation as a Protective Mechanism to Restrain Oxidative Stress in the Insulin-Resistant State in Skeletal Muscle of Rat Model of PCOS Subjected to Postnatal Overfeeding

“…PCOS is primarily recognized and treated as a reproductive disorder, but increasing attention is being paid to its metabolic implications since a large proportion of women with PCOS are obese and have insulin resistance. Previous studies indicate a close interaction between androgen excess and insulin resistance, but the exact mechanism and direction of causality between these conditions are still unclear [ 2 , 25 ].…”

“…Our results showed that only when DHT treatment and overfeeding were combined, decreased systemic insulin sensitivity and hyperinsulinemia were present, which is likely a compensatory mechanism for maintaining normal glucose levels [ 35 ]. While the combination of both factors is crucial for promoting hyperinsulinemia, the effect of postnatal overfeeding on the increased glucose excursion during ipGTT is more dominant, suggesting the predisposing role of prepubertal adiposity in the development of PCOS-associated insulin resistance [ 25 , 36 ].…”

“…Since skeletal muscles account for approximately 40% of total body mass and are capable of disposing of up to 80% of blood glucose, they are considered a key factor in driving the adverse metabolic phenotype in PCOS [ 2 , 24 , 25 ]. It is known that insulin resistance in skeletal muscle can occur years before the onset of systemic hyperglycemia [ 26 ].…”

“…The ability of a muscle to switch between the oxidation of lipids to oxidation of carbohydrates is known as metabolic flexibility. A significant decrease in metabolic flexibility is associated with both obesity and PCOS [ 25 ]. Metabolic inflexibility implies the inability of a muscle to adequately activate glucose metabolism in response to a glucose load.…”

“…Metabolic inflexibility implies the inability of a muscle to adequately activate glucose metabolism in response to a glucose load. However, defects in energy-sensing pathways, defects in mitochondrial fuel selection, intracellular or extracellular lipid accumulation leading to lipotoxicity, and oxidative stress are also factors that have been shown to impair metabolic flexibility and contribute to the development of insulin resistance in skeletal muscle [ 2 , 25 ].…”