Skeletal muscle fatty infiltration in the thigh, as assessed by MRI T2-weighted and 3-point Dixon sequences, is associated with poor performance on muscle function testing in patients with Cushing's syndrome in remission

Cushing's syndrome is characterized by marked central obesity and insulin insensitivity, effects opposite those seen with chronic AMP-activated protein kinase (AMPK) activation. This study was designed to determine whether chronic exposure to excess glucocorticoids influences LKB1/AMPK signaling in skeletal muscle. Corticosterone pellets were implanted subcutaneously in rats (hypercorticosteronemia, Hypercort) for 2 wk. Controls were sham operated and fed ad libitum or were sham operated and food restricted (pair-weighted group, Pair) to produce body weights similar to Hypercort rats. At the end of the 2-wk treatment period, rats were anesthetized, and the right gastrocnemius-plantaris (gastroc) and soleus muscles were removed. Left muscles were removed after electrical stimulation for 5 min. No significant differences were noted between treatment groups in ATP, creatine phosphate, or LKB1 activity. The α- and β-subunit isoforms were not significantly influenced in gastroc by corticosterone treatment. Expression of the γ3-subunit decreased, and γ1- and γ2-subunit expression increased. Both α2-AMPK and α1-AMPK activities were increased in the gastroc in response to electrical stimulation, but the magnitude of the increase was less for α2 in the Hypercort rats. Despite elevated plasma insulin and elevated plasma leptin in the Hypercort rats, phosphorylation of TBC1D1 was lower in both resting and stimulated muscle compared with controls. Malonyl-CoA content was elevated in gastroc muscles of resting Hypercort rats. These changes in response to excess glucocorticoids could be responsible, in part, for the decrease in insulin sensitivity and adiposity seen in Cushing's syndrome.

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Pleurihormonal Pituitary Adenomas Presenting as Acromegaly

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1227 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A602-A602

Author(s):

Megan Schwehr ◽

Mayumi Endo

Keyword(s):

Pituitary Adenoma ◽

Cushing’S Syndrome ◽

Cushing’S Disease ◽

Pituitary Adenomas ◽

Brain Mri ◽

Fatty Infiltration ◽

Cushing's Syndrome ◽

Cushing's Disease ◽

Peripheral Muscle ◽

Suppression Test

Abstract Background: Pleurihormonal pituitary adenomas represent 10-15% of all functioning pituitary adenomas1. One of the rarest combinations is ACTH-GH co-secretion with concomitant acromegaly and Cushing’s disease. Clinical Case: 30-year-old female with type 2 diabetes (A1c 11.4%) developed rapidly progressive peripheral neuropathy. Labs revealed a transaminitis. Hepatic ultrasound revealed fatty infiltration of the liver consistent with steatosis. Patient endorsed life-long “chicken legs”, buffalo hump, and easy bruising. She continued to have worsening paresthesias and stated her teeth were “more translucent”. At an endocrinology visit peripheral muscle wasting, atraumatic bruising at the ankles and toes,and striae on the abdomen, shoulders, breasts, and armpits were noted. She had also noted teeth separation and thinning over time and worsening diffuse joint aches. Lab results showed elevated cortisol value of 8.4 mcg/dl after 1 mg dexamethasone suppression test. 24-hour urine cortisol was elevated (87 ug/24 hrs, nl < 45 ug/24 hrs), confirming the diagnosis of Cushing’s syndrome. ACTH was inappropriately normal (56 pg/mL, nl 7.2 – 63 pg/mL), suggesting ACTH dependency. IGF-1 was elevated twice (328 ng/dL and 391 ng/dL, nl <303 ng/dL), and a GH suppression test was abnormal (GH 1.14 ng/mL at 90 minutes) confirming the diagnosis of acromegaly. Brain MRI revealed a cystic pituitary microadenoma (0.5 x 0.5 x 0.6 cm), and the patient underwent surgical resection via transnasal transsphenoidal pituitary surgery with total tumor removal. Immunostaining was positive for only synaptophysin and ACTH. Postoperative diagnosis of Cushing’s disease was made, with formal diagnosis of acromegaly pending improvement in follow-up IGF-1 levels. Literature reviews have revealed very few cases of pleurihormonal pituitary adenomas presenting with concomitant Cushing’s Syndrome and acromegaly. Roca et. al examined 17 studies which described 20 patients with this condition; only 4 presented with symptoms of both acromegaly and Cushing’s disease. In many cases previously reported, the clinical presentation of Cushing’s syndrome was subtle, often with subclinical Cushing’s syndrome, while patients had florid symptoms of acromegaly.1. Conclusion: This Cushing’s predominant case of a GH-ACTH co-secreting tumor is an incredibly rare presentation for this pleurihormonal pituitary adenoma, which is already a rare diagnosis. References: 1.Roca E, Mattogno PP, Porcelli T, Poliani L, Belotti F, Schreiber A, Maffezzoni F, Fontanella MM, Doglietto F. Plurihormonal ACTH-GH Pituitary Adenoma: Case Report and Systematic Literature Review. World Neurosurg. 2018 Jun;114:e158-e164. PMID: 29501516.

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Atrophy of Skeletal Muscle in Patients With Cushing's Syndrome

Archives of Neurology ◽

10.1001/archneur.1970.00480200024002 ◽

1970 ◽

Vol 22 (2) ◽

pp. 118-125 ◽

Cited By ~ 81

Author(s):

D. E. Pleasure ◽

G. O. Walsh ◽

W. K. Engel

Keyword(s):

Skeletal Muscle ◽

Cushing’S Syndrome ◽

Cushing's Syndrome

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Forkhead box O3 plays a role in skeletal muscle atrophy through expression of E3 ubiquitin ligases MuRF-1 and atrogin-1 in Cushing’s syndrome

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00389.2016 ◽

2017 ◽

Vol 312 (6) ◽

pp. E495-E507 ◽

Cited By ~ 15

Author(s):

Seol-Hee Kang ◽

Hae-Ahm Lee ◽

Mina Kim ◽

Eunjo Lee ◽

Uy Dong Sohn ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Cushing’S Syndrome ◽

Ubiquitin Ligases ◽

Cushing's Syndrome ◽

Skeletal Muscle Atrophy ◽

E3 Ubiquitin Ligases ◽

Sprague Dawley ◽

Muscle Weight ◽

Forkhead Box

Cushing’s syndrome is caused by overproduction of the adrenocorticotropic hormone (ACTH), which stimulates the adrenal grand to make cortisol. Skeletal muscle wasting occurs in pathophysiological response to Cushing’s syndrome. The forkhead box (FOX) protein family has been implicated as a key regulator of muscle loss under conditions such as diabetes and sepsis. However, the mechanistic role of the FOXO family in ACTH-induced muscle atrophy is not understood. We hypothesized that FOXO3a plays a role in muscle atrophy through expression of the E3 ubiquitin ligases, muscle RING finger protein-1 (MuRF-1), and atrogin-1 in Cushing’s syndrome. For establishment of a Cushing’s syndrome animal model, Sprague-Dawley rats were implanted with osmotic minipumps containing ACTH (40 ng·kg−1·day−1). ACTH infusion significantly reduced muscle weight. In ACTH-infused rats, MuRF-1, atrogin-1, and FOXO3a were upregulated and the FOXO3a promoter was targeted by the glucocorticoid receptor (GR). Transcriptional activity and expression of FOXO3a were significantly decreased by the GR antagonist RU486. Treatment with RU486 reduced MuRF-1 and atrogin-1 expression in accordance with reduced enrichment of FOXO3a and Pol II on the promoters. Knockdown of FOXO3a prevented dexamethasone-induced MuRF-1 and atrogin-1 expression. These results indicate that FOXO3a plays a role in muscle atrophy through expression of MuRF-1 and atrogin-1 in Cushing’s syndrome.

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EFFECT OF TREATMENT OF CUSHING'S SYNDROME ON SKELETAL MUSCLE STRUCTURE AND FUNCTION

Clinical Endocrinology ◽

10.1111/j.1365-2265.1983.tb00030.x ◽

1983 ◽

Vol 19 (4) ◽

pp. 547-556 ◽

Cited By ~ 19

Author(s):

A. A. KHALEELI ◽

D. J. BETTERIDGE ◽

R. H. T. EDWARDS ◽

J. M. ROUND ◽

E. J. ROSS

Keyword(s):

Skeletal Muscle ◽

Cushing’S Syndrome ◽

Cushing's Syndrome ◽

Structure And Function ◽

Muscle Structure ◽

Effect Of Treatment ◽

And Function

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Glucocorticoids Do Not Regulate the Expression of Proteolytic Genes in Skeletal Muscle from Cushing's Syndrome Patients

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.82.9.3161 ◽

1997 ◽

Vol 82 (9) ◽

pp. 3161-3164 ◽

Cited By ~ 11

Author(s):

C. RalliEre

Keyword(s):

Skeletal Muscle ◽

Cushing’S Syndrome ◽

Cushing's Syndrome

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Persisting Muscle Dysfunction in Cushing’s Syndrome Despite Biochemical Remission

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa625 ◽

2020 ◽

Vol 105 (12) ◽

pp. e4490-e4498 ◽

Cited By ~ 1

Author(s):

Frederick Vogel ◽

Leah T Braun ◽

German Rubinstein ◽

Stephanie Zopp ◽

Heike Künzel ◽

...

Keyword(s):

Muscle Strength ◽

Grip Strength ◽

Cushing’S Syndrome ◽

Muscle Function ◽

Tertiary Care ◽

Cushing's Syndrome ◽

Muscle Dysfunction ◽

Long Term Outcome

Abstract Context Glucocorticoid-induced myopathy is a characteristic symptom of endogenous Cushing’s syndrome (CS). Its long-term outcome is largely unknown. Objective To evaluate long-term muscle function following the remission of endogenous CS. Study Design Observational longitudinal cohort study. Setting Tertiary care hospitals and a specialized outpatient clinic. Patients As part of the prospective multicenter German Cushing’s Registry, we assessed muscle strength in patients with overt endogenous CS. We studied the patients at the time of diagnosis (n = 88), after 6 months (n = 69), and thereafter annually, following surgical remission over a period of up to 4 years (1 year: n = 55; 2 years: n = 34; 3 years: n = 29; 4 years: n = 22). Muscle function was evaluated by hand grip strength and by chair rising test. Results Grip strength was decreased to 83% of normal controls (100%) at the time of diagnosis. It further decreased to 71% after 6 months in remission (P ≤ 0.001) and showed no improvement during further follow-up compared with baseline. Chair rising test performance improved initially (8 seconds at baseline vs 7 seconds after 6 months, P = 0.004) but remained at this reduced level thereafter (7 seconds after 3 years vs 5 seconds in controls, P = 0.038). In multivariate analysis, we identified, as predictors for long-term muscle dysfunction, age, waist-to-hip ratio, and hemoglobin A1c at baseline. Furthermore, muscle strength during follow-up was strongly correlated with quality of life. Conclusion This study shows that CS-associated myopathy does not spontaneously resolve during remission. This calls for action to identify effective interventions to improve muscle dysfunction in this setting.

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