Graves' Disease With Initial Presentation of Thyrotoxic Periodic Paralysis.

Graves' disease is a common cause of hyperthyroidism. However, thyrotoxic periodic paralysis (TPP) is a rare complication of Graves' disease and is characterized by episodes of muscle weakness and hypokalemia in the setting of thyrotoxicosis. Episodic weakness and paralysis can be the first manifestation of Graves' disease with TPP despite lacking classic symptoms of hyperthyroidism and can be precipitated by risk factors such as a high carbohydrate diet and strenuous exercise. Although TPP is reversible with correction of hypokalemia and thyrotoxicosis, its uncommon presentation can lead to delay in diagnosis and treatment. Here, we describe a case of a 24-year-old Thai male who presented with proximal muscle weakness that progressed to frequent falls and inability to ambulate over the course of three days. He was found to have severe hypokalemia and diagnosed with TPP from underlying Graves' disease. He was treated with cautious replacement of potassium, a beta blocker, and methimazole to reverse thyrotoxicosis. He regained his ability to ambulate, and his weakness resolved after hypokalemia was corrected. He did not have a reoccurrence of muscle weakness the following 12 months after discharge by continuing treatment with methimazole. The varied clinical manifestations of TPP can make diagnosis challenging, but early recognition and treatment can prevent severe complications of this potentially life-threatening condition.

Disuse-induced muscle fibrosis, cellular senescence, and senescence-associated secretory phenotype in older adults are alleviated during re-ambulation with metformin pre-treatment.

Muscle inflammation and fibrosis underlie disuse-related complications and may contribute to impaired muscle recovery in aging. Cellular senescence is an emerging link between inflammation, extracellular matrix (ECM) remodeling and poor muscle recovery after disuse. In rodents, metformin has been shown to prevent cellular senescence/senescent associated secretory phenotype (SASP), inflammation, and fibrosis making it a potentially practical therapeutic solution. Thus, the purpose of this study was to determine in older adults if metformin monotherapy during bed rest could reduce muscle fibrosis and cellular senescence/SASP during the re-ambulation period. A two-arm controlled trial was utilized in healthy male and female older adults (n = 20; BMI: <30, age: 60 years+) randomized into either placebo or metformin treatment during a two-week run-in and 5 days of bedrest followed by metformin withdrawal during 7 days of recovery. We found that metformin-treated individuals had less type-I myofiber atrophy during disuse, reduced pro-inflammatory transcriptional profiles, and lower muscle collagen deposition during recovery. Collagen content and myofiber size corresponded to reduced whole muscle cellular senescence and SASP markers. Moreover, metformin treatment reduced primary muscle resident fibro-adipogenic progenitors (FAPs) senescent markers and promoted a shift in fibroblast fate to be less myofibroblast-like. Together, these results suggest that metformin pre-treatment improved ECM remodeling after disuse in older adults by possibly altering cellular senescence and SASP in skeletal muscle and in FAPs.

An accumulation of muscle macrophages is accompanied by altered insulin sensitivity after reduced activity and recovery.

BACKGROUND: Mechanisms underlying physical inactivity-induced insulin resistance are not well understood. In addition to a role in muscle repair, immune cell populations such as macrophages may regulate insulin sensitivity. AIM: The aim of this study was to examine if the dynamic changes in insulin sensitivity during and after recovery from reduced physical activity corresponded to changes in skeletal muscle macrophages. METHODS: In this prospective clinical study, we collected muscle biopsies from healthy older adults (70 ± 2 years, n = 12) before and during a hyperinsulinaemic-euglycaemic clamp and this occurred before (PRE) and after 2-week reduced physical activity (RA), and following 2-week of recovery (REC). Insulin sensitivity (hyperinsulinaemic-euglycaemic clamp), skeletal muscle mRNA expression of inflammatory markers, and immunofluorescent quantification of skeletal muscle macrophages, myofibre-specific satellite cell and capillary content were assessed. RESULTS: Insulin sensitivity was decreased following reduced activity and rebounded following recovery above PRE levels. We observed an increase (P < 0.01) in muscle macrophages (CD68+ CD206+ : 190 [55, 324]; CD11b+ CD206+ : 117 [28, 205]% change from PRE) and CD68 (2.4 [1.4, 3.4]-fold) and CCL2 (1.9 [1.3, 2.5]-fold) mRNA following RA concurrent with increased (P < 0.03) satellite cells (55 [6, 104]%) in slow-twitch myofibres. Moreover, the distance of satellite cells to the nearest capillary was increased 7.7 (1.7, 13.7) µm in fast-twitch myofibres at RA (P = 0.007). Changes in macrophages were positively associated with increased insulin sensitivity following RA (R > 0.57, P < 0.05). CONCLUSION: These findings suggested that a dynamic response of skeletal muscle macrophages following acute changes in physical activity in healthy older adults is related to insulin sensitivity.